Genetic polymorphisms associated with stroke, methods of detection and uses thereof

ABSTRACT

The present invention provides compositions and methods based on genetic polymorphisms that are associated with vascular diseases such as stroke. In particular, the present invention relates to genetic polymorphisms that have utility for such uses as predicting disease risk or predicting an individual&#39;s response to a treatment such as statins, including groups of polymorphisms that may be used as a signature marker set for such uses, as well as nucleic acid molecules containing the polymorphisms, variant proteins encoded by such nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and proteins, and methods of using the nucleic acid and proteins as well as methods of using reagents for their detection.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. non-provisionalapplication Ser. No. 15/790,581, filed on Oct. 23, 2017, which is acontinuation application of U.S. non-provisional application Ser. No.14/886,595, filed on Oct. 19, 2015, which is a continuation of U.S.non-provisional application Ser. No. 13/655,905, filed on Oct. 19, 2012,which is a continuation application of U.S. non-provisional applicationSer. No. 12/389,313, filed on Feb. 19, 2009, which claims priority toU.S. provisional application Ser. No. 61/066,584, filed on Feb. 20,2008, the contents of each of which are hereby incorporated by referencein their entirety into this application.

FIELD OF THE INVENTION

The present invention is in the field of vascular disease, particularlystroke, and drug response, particularly response to statin treatment. Inparticular, the present invention relates to specific single nucleotidepolymorphisms (SNPs) in the human genome, and their association withvascular disease, including but not limited to cerebrovascular diseasessuch as stroke, and/or variability in responsiveness to statin treatment(including preventive treatment) between different individuals. The SNPsdisclosed herein can be used, for example, as targets fordiagnostic/prognostic reagents as well as for therapeutic agents. Inparticular, the SNPs of the present invention are useful for identifyingan individual who is at an increased or decreased risk of having astroke, for early detection of stroke risk, for providing clinicallyimportant information for the prevention and/or treatment of stroke, forpredicting the seriousness or consequences of stroke in an individual,for determining the prognosis of an individual's recovery from stroke,for screening and selecting therapeutic agents, and for predicting apatient's response to therapeutic agents such as evaluating thelikelihood of an individual responding positively to statins,particularly for the treatment or prevention of stroke. The SNPsdisclosed herein are also useful for human identification applications.Methods, assays, kits, and reagents for detecting the presence of thesepolymorphisms and their encoded products are provided.

BACKGROUND OF THE INVENTION

Stroke and Other Vascular Diseases

Vascular diseases encompass a number of related pathologies includingcerebrovascular diseases such as stroke, as well as carotid arterydisease, coronary artery disease, peripheral artery disease, aorticaneurysm, and vascular dementia.

Stroke is a prevalent and serious cerebrovascular disease. It affects4.7 million individuals in the United States, with 500,000 first attacksand 200,000 recurrent cases yearly. Approximately one in four men andone in five women aged 45 years will have a stroke if they live to their85th year. About 25% of those who have a stroke die within a year. Infact, stroke is the third leading cause of mortality in the UnitedStates and is responsible for 170,000 deaths a year. Among those whosurvive a stroke attack, 30 to 50% do not regain functionalindependence. Stroke therefore is the most common cause of disabilityand the second leading cause of dementia (Heart Disease and StrokeStatistics—2004 Update, American Heart Association).

Stroke occurs when an artery bringing oxygen and nutrients to the braineither ruptures, causing hemorrhagic stroke, or gets occluded, causingischemic stroke. Ischemic stroke can be caused by thrombi formation atthe site of an atherosclerotic plaque rupture (this type of ischemicstroke is interchangeably referred to as thrombotic or atherothromboticstroke) or by emboli (clots) that have traveled from another part of thevasculature (this type of ischemic stroke is referred to as embolicstroke), often from the heart (this type of embolic stroke may bereferred to as cardioembolic stroke). In both ischemic and hemorrhagicstroke, a cascade of cellular changes due to ischemia or increasedcranial pressure leads to injuries or death of the brain cells. In theUnited States, the majority (about 80-90%) of stroke cases are ischemic(Rathore, et al., Stroke 33:2718-2721 ((2002)), including 30%large-vessel thrombotic (also referred to as large-vessel occlusivedisease), 20% small-vessel thrombotic (also referred to as small-vesselocclusive disease), and 30% embolic or cardiogenic (caused by a clotoriginating from elsewhere in the body, e.g., from blood pooling due toatrial fibrillation, or from carotid artery stenosis). The ischemic formof stroke results from obstruction of blood flow in cerebral bloodvessels, and it shares common pathological etiology with atherosclerosisand thrombosis.

About 10-20% of stroke cases are of the hemorrhagic type (Rathore, etal., Stroke 33:2718-2721 ((2002)), involving bleeding within or aroundthe brain. Bleeding within the brain is known as cerebral hemorrhage,which is often linked to high blood pressure. Bleeding into the meningessurrounding the brain is known as a subarachnoid hemorrhage, which couldbe caused by a ruptured cerebral aneurysm, an arteriovenousmalformation, or a head injury. The hemorrhagic stroke, although lessprevalent, poses a greater danger. Whereas about 8% of ischemic strokecases result in death within 30 days, about 38% of hemorrhagic strokecases result in death within the same time period (Collins, et al., J.Clin. Epidemiol. 56:81-87 (2003)).

Known risk factors for stroke can be divided into modifiable andnon-modifiable risk factors. Older age, male sex, black or Hispanicethnicity, and family history of stroke are non-modifiable risk factors.Modifiable risk factors include hypertension, smoking, increased insulinlevels, asymptomatic carotid disease, cardiac vessel disease, andhyperlipidemia.

Multiple reports based on twin studies (Brass et al., Stroke. 1992;23:221-223 and Bak et al., Stroke. 2002; 33:769-774) and family studies(Welin L, et al. N Engl J Med. 1987; 317:521-526 and Jousilahti et al.,Stroke. 1997; 28:1361-136) have shown that genetics contributes to riskof stroke independently of traditional risk factors. A number of geneticmarkers have been reported to be associated with stroke and someexamples of stroke-related markers include MTHFR, ACE, NOTCH3, IL-6,PON1, fibrinogen-beta, and lipoprotein lipase (Casas, et al., Arch.Neurol., 61:1652-1661 (2004)).

The acute nature of stroke leaves physicians with little time to preventor lessen the devastation of brain damage. Strategies to diminish theimpact of stroke include prevention and treatment with thrombolytic and,possibly, neuroprotective agents. The success of preventive measureswill depend on the identification of risk factors in individual patientsand means to modulate their impact.

Although some risk factors for stroke are not modifiable, such as ageand family history, other underlying pathology or risk factors of strokesuch as atherosclerosis, hypertension, smoking, diabetes, aneurysm, andatrial fibrillation, are chronic and amenable to effective life-stylechanges, pharmacological, and interventional as well as surgicaltreatments. Early recognition of patients with informative risk factors,and especially those with a family history, using a non-invasive test ofgenetic markers associated with stroke will enable physicians to targetthe highest risk individuals for aggressive risk reduction.

Thus, there is a need for the identification of new genetic markers thatare predictive of an individual's predisposition to the development ofstroke and other vascular diseases. Furthermore, the discovery ofgenetic markers which are useful in identifying individuals who are atan increased risk of having a stroke may lead to, for example, betterpreventive and therapeutic strategies, economic models, and health carepolicy decisions.

Reduction of coronary and cerebrovascular events and total mortality bytreatment with HMG-CoA reductase inhibitors (statins) has beendemonstrated in a number of randomized, double blinded,placebo-controlled prospective trials (Waters, D. D., Clin Cardiol,2001. 24(8 Suppl): p. 1113-7, Singh, B. K. and J. L. Mehta, Curr OpinCardiol, 2002. 17(5): p. 503-11). These drugs have their primary effectthrough the inhibition of hepatic cholesterol synthesis, therebyupregulating LDL receptors in the liver. The resultant increase in LDLcatabolism results in decreased circulating LDL, a major risk factor forvascular disease.

In addition to LDL-lowering, a variety of potential non-lipid loweringeffects have been suggested to play a role in cardiovascular riskreduction by statins. These include anti-inflammatory effects on variousvascular cell types including foam cell macrophages, improvedendothelial responses, inhibition of platelet reactivity therebydecreasing hypercoaguability, and many others (Puddu, P., G. M. Puddu,and A. Muscari, Acta Cardiol, 2001. 56(4): p. 225-31, Albert, M. A., etal., JAMA, 2001. 286(1): p. 64-70, Rosenson, R. S., Curr Cardiol Rep,1999. 1(3): p. 225-32, Dangas, G., et al., Thromb Haemost, 2000. 83(5):p. 688-92, Crisby, M., Drugs Today (Barc), 2003. 39(2): p. 137-43, Liao,J. K., Int J Clin Pract Suppl, 2003(134): p. 51-7). However, becausehypercholesterolemia is a factor in many of these additionalpathophysiologic mechanisms that are reversed by statins, many of thesestatin benefits may be a consequence of LDL lowering.

Statins can be divided into two types according to their physicochemicaland pharmacokinetic properties. Statins such as lovastatin, simvastatin,atorvastatin, and cerevastatin are hydrophobic in nature and, as such,diffuse across membranes and thus are highly cell permeable. Hydrophilicstatins such as pravastatin are more polar, such that they utilizespecific cell surface transporters for cellular uptake (Ziegler, K. andW. Stunkel, Biochim Biophys Acta, 1992. 1139(3): p. 203-9, Yamazaki, M.,et al., Am J Physiol, 1993. 264(1 Pt 1): p. G36-44, Komai, T., et al.,Biochem Pharmacol, 1992. 43(4): p. 667-70). The latter statin utilizes atransporter, OATP2, the tissue distribution of which is confined to theliver and, therefore, they are relatively hepato-specific inhibitors(Hsiang, B., et al., J Biol Chem, 1999. 274(52): p. 37161-8). The formerstatins, which do not utilize specific transport mechanisms, areavailable to all cells and they can directly impact a much broaderspectrum of cells and tissues. These differences in properties mayinfluence the spectrum of activities that each statin possesses.Pravastatin, for instance, has a low myopathic potential in animalmodels and myocyte cultures compared to other hydrophobic statins(Masters, B. A., et al., Toxicol Appl Pharmacol, 1995. 131(1): p.163-74. Nakahara, K., et al., Toxicol Appl Pharmacol, 1998. 152(1): p.99-106, Reijneveld, J. C., et al., Pediatr Res, 1996. 39(6): p.1028-35).

Evidence from gene association studies is accumulating to indicate thatresponses to drugs are, indeed, at least partly under genetic control.As such, pharmacogenetics—the study of variability in drug responsesattributed to hereditary factors in different populations—maysignificantly assist in providing answers toward meeting this challenge(Roses, A. D., Nature, 2000. 405(6788): p. 857-65, Mooser, V., et al., JThromb Haemost, 2003. 1(7): p. 1398-1402, Humma, L. M. and S. G. Terra,Am. J. Health Syst Pharm, 2002. 59(13): p. 1241-52). Numerousassociations have been reported between selected genotypes, as definedby SNPs and other sequence variations, and specific responses tocardiovascular drugs. Polymorphisms in several genes have been suggestedto influence responses to statins including CETP (Kuivenhoven, J. A., etal., N Engl J Med, 1998. 338(2): p. 86-93), beta-fibrinogen (de Maat, M.P., et al., Arterioscler Thromb Vasc Biol, 1998. 18(2): p. 265-71),hepatic lipase (Zambon, A., et al., Circulation, 2001. 103(6): p.792-8), lipoprotein lipase (Jukema, J. W., et al., Circulation, 1996.94(8): p. 1913-8), glycoprotein Ma (Bray, P. F., et al., Am J Cardiol,2001. 88(4): p. 347-52), stromelysin-1 (de Maat, M. P., et al., Am JCardiol, 1999. 83(6): p. 852-6), and apolipoprotein E (Gerdes, L. U., etal., Circulation, 2000. 101(12): p. 1366-71, Pedro-Botet, J., et al.,Atherosclerosis, 2001. 158(1): p. 183-93). Some of these variants wereshown to effect clinical events while others were associated withchanges in surrogate endpoints.

Thus, there is also a need to identify genetic markers for stratifyingstroke patients based on their likelihood of responding to drug therapy,particularly statin treatment.

SNPs

The genomes of all organisms undergo spontaneous mutation in the courseof their continuing evolution, generating variant forms of progenitorgenetic sequences (Gusella, Ann. Rev. Biochem. 55, 831-854 (1986)). Avariant form may confer an evolutionary advantage or disadvantagerelative to a progenitor form or may be neutral. In some instances, avariant form confers an evolutionary advantage to the species and iseventually incorporated into the DNA of many or most members of thespecies and effectively becomes the progenitor form. Additionally, theeffects of a variant form may be both beneficial and detrimental,depending on the circumstances. For example, a heterozygous sickle cellmutation confers resistance to malaria, but a homozygous sickle cellmutation is usually lethal. In many cases, both progenitor and variantforms survive and co-exist in a species population. The coexistence ofmultiple forms of a genetic sequence gives rise to geneticpolymorphisms, including SNPs.

Approximately 90% of all polymorphisms in the human genome are SNPs.SNPs are single base positions in DNA at which different alleles, oralternative nucleotides, exist in a population. The SNP position(interchangeably referred to herein as SNP, SNP site, SNP locus, SNPmarker, or marker) is usually preceded by and followed by highlyconserved sequences of the allele (e.g., sequences that vary in lessthan 1/100 or 1/1000 members of the populations). An individual may behomozygous or heterozygous for an allele at each SNP position. A SNPcan, in some instances, be referred to as a “cSNP” to denote that thenucleotide sequence containing the SNP is an amino acid coding sequence.

A SNP may arise from a substitution of one nucleotide for another at thepolymorphic site. Substitutions can be transitions or transversions. Atransition is the replacement of one purine nucleotide by another purinenucleotide, or one pyrimidine by another pyrimidine. A transversion isthe replacement of a purine by a pyrimidine, or vice versa. A SNP mayalso be a single base insertion or deletion variant referred to as an“indel” (Weber et al., “Human diallelic insertion/deletionpolymorphisms”, Am J Hum Genet 2002 October; 71(4):855-82).

A synonymous codon change, or silent mutation/SNP (terms such as “SNP”,“polymorphism”, “mutation”, “mutant”, “variation”, and “variant” areused herein interchangeably), is one that does not result in a change ofamino acid due to the degeneracy of the genetic code. A substitutionthat changes a codon coding for one amino acid to a codon coding for adifferent amino acid (i.e., a non-synonymous codon change) is referredto as a missense mutation. A nonsense mutation results in a type ofnon-synonymous codon change in which a stop codon is formed, therebyleading to premature termination of a polypeptide chain and a truncatedprotein. A read-through mutation is another type of non-synonymous codonchange that causes the destruction of a stop codon, thereby resulting inan extended polypeptide product. While SNPs can be bi-, tri-, ortetra-allelic, the vast majority of the SNPs are bi-allelic, and arethus often referred to as “bi-allelic markers”, or “di-allelic markers”.

As used herein, references to SNPs and SNP genotypes include individualSNPs and/or haplotypes, which are groups of SNPs that are generallyinherited together. Haplotypes can have stronger correlations withdiseases or other phenotypic effects compared with individual SNPs, andtherefore may provide increased diagnostic accuracy in some cases(Stephens et al. Science 293, 489-493, 20 Jul. 2001). As used herein,the term “haplotype” refers to a set of two or more alleles on a singlechromosome. The term “diplotype” refers to a combination of twohaplotypes that a diploid individual carries. The term “doublediplotype”, also called “two-locus diplotype”, refers to a combinationof diplotypes at two distinct loci for an individual.

Causative SNPs are those SNPs that produce alterations in geneexpression or in the expression, structure, and/or function of a geneproduct, and therefore are most predictive of a possible clinicalphenotype. One such class includes SNPs falling within regions of genesencoding a polypeptide product, i.e. cSNPs. These SNPs may result in analteration of the amino acid sequence of the polypeptide product (i.e.,non-synonymous codon changes) and give rise to the expression of adefective or other variant protein. Furthermore, in the case of nonsensemutations, a SNP may lead to premature termination of a polypeptideproduct. Such variant products can result in a pathological condition,e.g., genetic disease. Examples of genes in which a SNP within a codingsequence causes a genetic disease include sickle cell anemia and cysticfibrosis.

Causative SNPs do not necessarily have to occur in coding regions;causative SNPs can occur in, for example, any genetic region that canultimately affect the expression, structure, and/or activity of theprotein encoded by a nucleic acid. Such genetic regions include, forexample, those involved in transcription, such as SNPs in transcriptionfactor binding domains, SNPs in promoter regions, in areas involved intranscript processing, such as SNPs at intron-exon boundaries that maycause defective splicing, or SNPs in mRNA processing signal sequencessuch as polyadenylation signal regions. Some SNPs that are not causativeSNPs nevertheless are in close association with, and therefore segregatewith, a disease-causing sequence. In this situation, the presence of aSNP correlates with the presence of, or predisposition to, or anincreased risk in developing the disease. These SNPs, although notcausative, are nonetheless also useful for diagnostics, diseasepredisposition screening, and other uses.

An association study of a SNP and a specific disorder involvesdetermining the presence or frequency of the SNP allele in biologicalsamples from individuals with the disorder of interest, such as strokeand related pathologies and comparing the information to that ofcontrols (i.e., individuals who do not have the disorder; controls maybe also referred to as “healthy” or “normal” individuals) who arepreferably of similar age and race. The appropriate selection ofpatients and controls is important to the success of SNP associationstudies. Therefore, a pool of individuals with well-characterizedphenotypes is extremely desirable.

A SNP may be screened in diseased tissue samples or any biologicalsample obtained from a diseased individual, and compared to controlsamples, and selected for its increased (or decreased) occurrence in aspecific pathological condition, such as stroke. Once a statisticallysignificant association is established between one or more SNP(s) and apathological condition (or other phenotype) of interest, then the regionaround the SNP can optionally be thoroughly screened to identify thecausative genetic locus/sequence(s) (e.g., causative SNP/mutation, gene,regulatory region, etc.) that influences the pathological condition orphenotype. Association studies may be conducted within the generalpopulation and are not limited to studies performed on relatedindividuals in affected families (linkage studies).

Clinical trials have shown that patient response to treatment withpharmaceuticals is often heterogeneous. There is a continuing need toimprove pharmaceutical agent design and therapy. In that regard, SNPscan be used to identify patients most suited to therapy with particularpharmaceutical agents (this is often termed “pharmacogenomics”).Similarly, SNPs can be used to exclude patients from certain treatmentdue to the patient's increased likelihood of developing toxic sideeffects or their likelihood of not responding to the treatment.Pharmacogenomics can also be used in pharmaceutical research to assistthe drug development and selection process. (Linder et al. (1997),Clinical Chemistry, 43, 254; Marshall (1997), Nature Biotechnology, 15,1249; International Patent Application WO 97/40462, Spectra Biomedical;and Schafer et al. (1998), Nature Biotechnology, 16: 3).

SUMMARY OF THE INVENTION

The present invention relates to the identification of SNPs, uniquecombinations of SNPs, and haplotypes or diplotypes of SNPs, that areassociated with stroke (e.g., an increased or decreased risk of having astroke), and/or with drug response, particularly response to statintreatment (including preventive treatment) such as for the treatment orprevention of stroke. The polymorphisms disclosed herein are directlyuseful as targets for the design of diagnostic and prognostic reagentsand the development of therapeutic and preventive agents, such as foruse in determining an individual's predisposition to having a stroke,and for treatment or prevention of stroke and related pathologies suchas other vascular diseases, as well as for predicting a patient'sresponse to therapeutic agents such as statins, particularly for thetreatment or prevention of stroke. Furthermore, the polymorphismsdisclosed herein may also be used for predicting an individual'sresponsiveness to statins for the treatment or prevention of disordersother than stroke, such as cancer, and may also be used for predictingan individual's responsiveness to drugs other than statins that are usedto treat or prevent stroke.

Based on the identification of SNPs associated with stroke, and/orresponse to statin treatment, the present invention also providesmethods of detecting these variants as well as the design andpreparation of detection reagents needed to accomplish this task. Theinvention specifically provides, for example, SNPs associated withstroke, and/or responsiveness to statin treatment, isolated nucleic acidmolecules (including DNA and RNA molecules) containing these SNPs,variant proteins encoded by nucleic acid molecules containing such SNPs,antibodies to the encoded variant proteins, computer-based and datastorage systems containing the novel SNP information, methods ofdetecting these SNPs in a test sample, methods of identifyingindividuals who have an altered (i.e., increased or decreased) risk ofhaving a first or recurrent stroke, methods for prognosing the severityor consequences of stroke, methods of treating an individual who has anincreased risk for stroke, and methods for identifying individuals(e.g., determining a particular individual's likelihood) who have analtered (i.e., increased or decreased) likelihood of responding tostatin treatment (or more or less likely to experience undesirable sideeffects from a treatment), particularly statin treatment of stroke,based on the presence or absence of one or more particular nucleotides(alleles) at one or more SNPs disclosed herein or the detection of oneor more encoded variant products (e.g., variant mRNA transcripts orvariant proteins), methods of screening for compounds useful in thetreatment or prevention of a disorder associated with a variantgene/protein, compounds identified by these methods, methods of treatingor preventing disorders mediated by a variant gene/protein, etc. Thepresent invention also provides methods for identifying individuals whopossess SNPs that are associated with an increased risk of stroke, andyet can benefit from being treated with statin because statin treatmentcan lower their risk of stroke.

The exemplary utilities described herein for the stroke-associated SNPsand statin response-associated SNPs disclosed herein apply to both first(primary) and recurrent stroke. For example, the SNPs disclosed hereincan be used for determining the risk for a first stroke in an individualwho has never had a stroke in the past, and can also be used fordetermining the risk for a recurrent stroke in an individual who haspreviously had a stroke.

The present invention further provides methods for selecting orformulating a treatment regimen (e.g., methods for determining whetheror not to administer statin treatment to an individual who haspreviously had a stroke, or who is at risk for having a stroke in thefuture, methods for selecting a particular statin-based treatmentregimen such as dosage and frequency of administration of statin, or aparticular form/type of statin such as a particular pharmaceuticalformulation or statin compound, methods for administering analternative, non-statin-based treatment to individuals who are predictedto be unlikely to respond positively to statin treatment, etc.), andmethods for determining the likelihood of experiencing toxicity or otherundesirable side effects from statin treatment, etc. The presentinvention also provides methods for selecting individuals to whom astatin or other therapeutic will be administered based on theindividual's genotype, and methods for selecting individuals for aclinical trial of a statin or other therapeutic agent based on thegenotypes of the individuals (e.g., selecting individuals to participatein the trial who are most likely to respond positively from the statintreatment and/or excluding individuals from the trial who are unlikelyto respond positively from the statin treatment). The present inventionfurther provides methods for reducing an individual's risk of having astroke by administering statin treatment, including preventing a firstor recurrent stroke by administering statin treatment, when saidindividual carries one or more SNPs identified herein as beingassociated with stroke risk or stroke statin response.

In certain exemplary embodiments of the invention, the SNP is selectedfrom the group consisting of the following (the name of the gene, orchromosome, that contains the SNP is indicated in parentheses):rs3900940/hCV7425232 (MYH15), rs3814843/hCV11476411 (CALM1),rs2200733/hCV16158671 (chromosome 4q25), and rs10757274/hCV26505812(chromosome 9p21), and combinations of any number of these SNPs, as wellas any of these SNP in combination with other genetic markers. Exemplaryembodiments of the invention provide compositions (e.g., detectionreagents and kits) and methods of using these SNPs for stroke-relatedutilities, such as for determining an individual's risk of having astroke or whether an individual will benefit from treatment with statinsor other therapies. For example, certain embodiments provide methods ofusing any of rs3900940/hCV7425232 (MYH15), rs3814843/hCV11476411(CALM1), rs2200733/hCV16158671 (chromosome 4q25), and/orrs10757274/hCV26505812 (chromosome 9p21) for determining stroke risk inan individual, and methods of using rs10757274/hCV26505812 (chromosome9p21) for determining whether an individual will benefit from statintreatment.

In Tables 1-2, the present invention provides gene information,transcript sequences (SEQ ID NOS:1-80), encoded amino acid sequences(SEQ ID NOS:81-160), genomic sequences (SEQ ID NOS:260-435),transcript-based context sequences (SEQ ID NOS:161-259) andgenomic-based context sequences (SEQ ID NOS:436-1566) that contain theSNPs of the present invention, and extensive SNP information thatincludes observed alleles, allele frequencies, populations/ethnic groupsin which alleles have been observed, information about the type of SNPand corresponding functional effect, and, for cSNPs, information aboutthe encoded polypeptide product. The transcript sequences (SEQ IDNOS:1-80), amino acid sequences (SEQ ID NOS:81-160), genomic sequences(SEQ ID NOS:260-435), transcript-based SNP context sequences (SEQ IDNOS:161-259), and genomic-based SNP context sequences (SEQ IDNOS:436-1566) are also provided in the Sequence Listing.

In certain exemplary embodiments, the invention provide methods foridentifying an individual who has an altered risk for having a first orrecurrent stroke, in which the method comprises detecting a singlenucleotide polymorphism (SNP) in any of the nucleotide sequences of SEQID NOS:1-80 and 161-1566, particularly as represented by any of thegenomic context sequences of SEQ ID NOS:436-1566, in said individual'snucleic acids, wherein the SNP is specified in Table 1 and/or Table 2,and the presence of the SNP is indicative of an altered risk for strokein said individual. In certain exemplary embodiment of the presentinvention, SNPs that occur naturally in the human genome are provided asisolated nucleic acid molecules. These SNPs are associated with strokeand related pathologies such as other vascular diseases. Other vasculardiseases include, but are not limited to, cerebrovascular disease,carotid artery disease, coronary artery disease, peripheral arterydisease, aortic aneurysm, and vascular dementia. In particular the SNPsare associated with either an increased or decreased risk of having astroke. As such, they can have a variety of uses in the diagnosis and/ortreatment of stroke and related pathologies. One aspect of the presentinvention relates to an isolated nucleic acid molecule comprising anucleotide sequence in which at least one nucleotide is a SNP that isproprietary to Applera, or Celera. In an alternative embodiment, anucleic acid of the invention is an amplified polynucleotide, which isproduced by amplification of a SNP-containing nucleic acid template. Inanother embodiment, the invention provides for a variant protein that isencoded by a nucleic acid molecule containing a SNP disclosed herein.

In yet another embodiment of the invention, a reagent for detecting aSNP in the context of its naturally-occurring flanking nucleotidesequences (which can be, e.g., either DNA or mRNA) is provided. Inparticular, such a reagent may be in the form of, for example, ahybridization probe or an amplification primer that is useful in thespecific detection of a SNP of interest. In an alternative embodiment, aprotein detection reagent is used to detect a variant protein that isencoded by a nucleic acid molecule containing a SNP disclosed herein. Apreferred embodiment of a protein detection reagent is an antibody or anantigen-reactive antibody fragment.

Various embodiments of the invention also provide kits comprising SNPdetection reagents, and methods for detecting the SNPs disclosed hereinby employing detection reagents. In a specific embodiment, the presentinvention provides for a method of identifying an individual having anincreased or decreased risk of having a stroke by detecting the presenceor absence of one or more SNP alleles disclosed herein. Preferably, theSNP allele can be an allele of a SNP selected from the group consistingof the following (the name of the gene, or chromosome, that contains theSNP is indicated in parentheses): rs3900940/hCV7425232 (MYH15),rs3814843/hCV11476411 (CALM1), rs2200733/hCV16158671 (chromosome 4q25),and rs10757274/hCV26505812 (chromosome 9p21), and combinations of anynumber of these SNPs, as well as any of these SNP in combination withother genetic markers.

In another embodiment, a method for diagnosing stroke or relatedpathologies by detecting the presence or absence of one or more SNPs orSNP alleles disclosed herein is provided. In another embodiment, theinvention provides a method of identifying an individual having analtered (either increased or decreased) risk of having a stroke bydetecting the presence or absence of one or more SNPs or SNP allelesdisclosed herein. Thus, an exemplary embodiment of the inventionprovides a method of identifying an individual who has an increased riskof having a stroke by determining which nucleotide (allele) is presentat one or more SNPs disclosed herein. An alternative exemplaryembodiment of the invention provides a method of identifying anindividual who has a decreased risk of having a stroke by determiningwhich nucleotide (allele) is present at one or more SNPs disclosedherein.

The nucleic acid molecules of the invention can be inserted in anexpression vector, such as to produce a variant protein in a host cell.Thus, the present invention also provides for a vector comprising aSNP-containing nucleic acid molecule, genetically-engineered host cellscontaining the vector, and methods for expressing a recombinant variantprotein using such host cells. In another specific embodiment, the hostcells, SNP-containing nucleic acid molecules, and/or variant proteinscan be used as targets in a method for screening and identifyingtherapeutic agents or pharmaceutical compounds useful in the treatmentof stroke and related pathologies such as other vascular diseases.

An aspect of this invention is a method for treating or preventing afirst or recurrent stroke in a human subject wherein said human subjectharbors a SNP, gene, transcript, and/or encoded protein identified inTables 1-2, which method comprises administering to said human subject atherapeutically or prophylactically effective amount of one or moreagents (e.g., statins) counteracting the effects of the disease, such asby inhibiting (or stimulating) the activity of the gene, transcript,and/or encoded protein identified in Tables 1-2.

Another aspect of this invention is a method for identifying an agentuseful in therapeutically or prophylactically treating stroke andrelated pathologies in a human subject wherein said human subjectharbors a SNP, gene, transcript, and/or encoded protein identified inTables 1-2, which method comprises contacting the gene, transcript, orencoded protein with a candidate agent (e.g., a statin) under conditionssuitable to allow formation of a binding complex between the gene,transcript, or encoded protein and the candidate agent and detecting theformation of the binding complex, wherein the presence of the complexidentifies said agent.

Another aspect of this invention is a method for treating stroke andrelated pathologies in a human subject, which method comprises:

(i) determining that said human subject harbors a SNP, gene, transcript,and/or encoded protein identified in Tables 1-2, and

(ii) administering to said subject a therapeutically or prophylacticallyeffective amount of one or more agents (e.g., statins) counteracting theeffects of the disease.

Yet another aspect of this invention is a method for evaluating thesuitability of a patient for stroke treatment comprising determining thegenotype of said patient with respect to a particular set of SNPmarkers, said SNP markers comprising a plurality of individual SNPs(e.g., about 2-7 SNPs) in Tables 1-2, and calculating a score using anappropriate algorithm based on the genotype of said patient, theresulting score being indicative of the suitability of said patientundergoing stroke treatment.

Another aspect of the invention is a method of treating a stroke patientcomprising administering an appropriate drug in a therapeuticallyeffective amount to said stroke patient whose genotype has been shown tocontain a plurality of SNPs as described in Table 1 or Table 2.

Another aspect of the invention is a method for identifying a human whois likely to benefit from statin treatment (as used herein, “treatment”includes preventive as well as therapeutic treatment), in which themethod comprises detecting the presence of a statin response-associatedSNP (e.g., an allele associated with increased statin benefit) disclosedherein in said human's nucleic acids, wherein the presence of the SNPindicates that said human is likely to benefit from statin treatment.

Another aspect of the invention is a method for identifying a human whois likely to benefit from statin treatment, in which the methodcomprises detecting the presence of a SNP that is in LD with a statinresponse-associated SNP disclosed herein in said human's nucleic acids,wherein the presence of the SNP indicates that said human is likely tobenefit from statin treatment.

Exemplary embodiments of the invention include methods of using a statinresponse-associated SNP disclosed herein for determining whether anindividual will benefit from statin treatment (e.g., determining whetheran individual should be administered statin to reduce their likelihoodof having a stroke). The statin response-associated SNPs disclosed herecan be used for predicting response to any statin (HMG-CoA reductaseinhibitors), including but not limited to, pravastatin (Pravachol®),atorvastatin (Lipitor®), storvastatin, rosuvastatin (Crestor®),fluvastatin (Lescol®), lovastatin (Mevacor®), and simvastatin (Zocor®),as well as combination therapies that include a statin such assimvastatin+ezetimibe (Vytorin®), lovastatin+niacin extended-release(Advicor®), and atorvastatin+amlodipine besylate (Caduet®).

In certain exemplary embodiments of the invention, methods are directedto the determination of which patients would have greater protectionagainst stroke when they are given an intensive statin treatment ascompared to a standard statin treatment. In certain embodiments, thestatin can comprise a statin selected from the group consisting ofatorvastatin, pravastatin, and storvastatin. In certain embodiments,intensive statin treatment comprises administering higher doses of astatin and/or increasing the frequency of statin administration ascompared with standard statin treatment. In certain further embodiments,intensive statin treatment can utilize a different type of statin thanstandard statin treatment; for example, atorvastatin can be used forintensive statin treatment and pravastatin can be used for standardstatin treatment.

Many other uses and advantages of the present invention will be apparentto those skilled in the art upon review of the detailed description ofthe preferred embodiments herein. Solely for clarity of discussion, theinvention is described in the sections below by way of non-limitingexamples.

Description of the File Contained on the CD-R Named CD000022ORD-CDR

The CD-R named CD000022ORD-CDR contains the following text (ASCII) file:

1) File SEQLIST_CD000022ORD.txt provides the Sequence Listing. TheSequence Listing provides the transcript sequences (SEQ ID NOS:1-80) andprotein sequences (SEQ ID NOS:81-160) as shown in Table 1, and genomicsequences (SEQ ID NOS:260-435) as shown in Table 2, for eachstroke-associated gene that contains one or more SNPs of the presentinvention. Also provided in the Sequence Listing are context sequencesflanking each SNP, including both transcript-based context sequences asshown in Table 1 (SEQ ID NOS:161-259) and genomic-based contextsequences as shown in Table 2 (SEQ ID NOS:436-1566). The contextsequences generally provide 100 bp upstream (5′) and 100 bp downstream(3′) of each SNP, with the SNP in the middle of the context sequence,for a total of 200 bp of context sequence surrounding each SNP.

File SEQLIST_CD000022ORD.txt is 21,295 KB in size, and was created onFeb. 18, 2009. A computer readable format of the sequence listing isalso submitted herein on a separate CDR labeled CRF. The informationrecorded in the CRF CDR is identical to the sequence listing as providedon the CDR Duplicate Copy 1 and Duplicate Copy 2.

The material contained on the CD-R labeled CRF is hereby incorporated byreference pursuant to 37 CFR 1.77(b)(4).

LENGTHY TABLES The patent contains a lengthy table section. A copy ofthe table is available in electronic form from the USPTO web site(https://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US11401555B2).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

Description of Table 1 and Table 2

Table 1 and Table 2 disclose the SNP and associatedgene/transcript/protein information of the present invention. For eachgene, Table 1 and Table 2 each provide a header containinggene/transcript/protein information, followed by a transcript andprotein sequence (in Table 1) or genomic sequence (in Table 2), and thenSNP information regarding each SNP found in that gene/transcript.

NOTE: SNPs may be included in both Table 1 and Table 2; Table 1 presentsthe SNPs relative to their transcript sequences and encoded proteinsequences, whereas Table 2 presents the SNPs relative to their genomicsequences (in some instances Table 2 may also include, after the lastgene sequence, genomic sequences of one or more intergenic regions, aswell as SNP context sequences and other SNP information for any SNPsthat lie within these intergenic regions). SNPs can readily becross-referenced between Tables based on their hCV (or, in someinstances, hDV) identification numbers.

The gene/transcript/protein information includes:

-   -   a gene number (1 through n, where n=the total number of genes in        the Table)    -   a Celera hCG and UID internal identification numbers for the        gene    -   a Celera hCT and UID internal identification numbers for the        transcript (Table 1 only)    -   a public Genbank accession number (e.g., RefSeq NM number) for        the transcript (Table 1 only)    -   a Celera hCP and UID internal identification numbers for the        protein encoded by the hCT transcript (Table 1 only)    -   a public Genbank accession number (e.g., RefSeq NP number) for        the protein (Table 1 only)    -   an art-known gene symbol    -   an art-known gene/protein name    -   Celera genomic axis position (indicating start nucleotide        position-stop nucleotide position)    -   the chromosome number of the chromosome on which the gene is        located    -   an OMIM (Online Mendelian Inheritance in Man; Johns Hopkins        University/NCBI) public reference number for obtaining further        information regarding the medical significance of each gene    -   alternative gene/protein name(s) and/or symbol(s) in the OMIM        entry

NOTE: Due to the presence of alternative splice forms, multipletranscript/protein entries can be provided for a single gene entry inTable 1; i.e., for a single Gene Number, multiple entries may beprovided in series that differ in their transcript/protein informationand sequences.

Following the gene/transcript/protein information is a transcriptsequence and protein sequence (in Table 1), or a genomic sequence (inTable 2), for each gene, as follows:

-   -   transcript sequence (Table 1 only) (corresponding to SEQ ID        NOS:1-80 of the Sequence Listing), with SNPs identified by their        IUB codes (transcript sequences can include 5′ UTR, protein        coding, and 3′ UTR regions). (NOTE: If there are differences        between the nucleotide sequence of the hCT transcript and the        corresponding public transcript sequence identified by the        Genbank accession number, the hCT transcript sequence (and        encoded protein) is provided, unless the public sequence is a        RefSeq transcript sequence identified by an NM number, in which        case the RefSeq NM transcript sequence (and encoded protein) is        provided. However, whether the hCT transcript or RefSeq NM        transcript is used as the transcript sequence, the disclosed        SNPs are represented by their IUB codes within the transcript.)    -   the encoded protein sequence (Table 1 only) (corresponding to        SEQ ID NOS:81-160 of the Sequence Listing)    -   the genomic sequence of the gene (Table 2 only), including 6 kb        on each side of the gene boundaries (i.e., 6 kb on the 5′ side        of the gene plus 6 kb on the 3′ side of the gene) (corresponding        to SEQ ID NOS:260-435 of the Sequence Listing).

After the last gene sequence, Table 2 may include additional genomicsequences of intergenic regions (in such instances, these sequences areidentified as “Intergenic region:” followed by a numericalidentification number), as well as SNP context sequences and other SNPinformation for any SNPs that lie within each intergenic region (andsuch SNPs are identified as “INTERGENIC” for SNP type).

NOTE: The transcript, protein, and transcript-based SNP contextsequences are provided in both Table 1 and in the Sequence Listing. Thegenomic and genomic-based SNP context sequences are provided in bothTable 2 and in the Sequence Listing. SEQ ID NOS are indicated in Table 1for each transcript sequence (SEQ ID NOS:1-80), protein sequence (SEQ IDNOS:81-160), and transcript-based SNP context sequence (SEQ IDNOS:161-259), and SEQ ID NOS are indicated in Table 2 for each genomicsequence (SEQ ID NOS:260-435), and genomic-based SNP context sequence(SEQ ID NOS:436-1566).

The SNP information includes:

-   -   context sequence (taken from the transcript sequence in Table 1,        and taken from the genomic sequence in Table 2) with the SNP        represented by its IUB code, including 100 bp upstream (5′) of        the SNP position plus 100 bp downstream (3′) of the SNP position        (the transcript-based SNP context sequences in Table 1 are        provided in the Sequence Listing as SEQ ID NOS:161-259; the        genomic-based SNP context sequences in Table 2 are provided in        the Sequence Listing as SEQ ID NOS:436-1566).    -   Celera hCV internal identification number for the SNP (in some        instances, an “hDV” number is given instead of an “hCV” number)    -   SNP position [position of the SNP within the given transcript        sequence (Table 1) or within the given genomic sequence (Table        2)]    -   SNP source (may include any combination of one or more of the        following five codes, depending on which internal sequencing        projects and/or public databases the SNP has been observed in:        “Applera”=SNP observed during the re-sequencing of genes and        regulatory regions of 39 individuals, “Celera”=SNP observed        during shotgun sequencing and assembly of the Celera human        genome sequence, “Celera Diagnostics”=SNP observed during        re-sequencing of nucleic acid samples from individuals who have        a disease, “dbSNP”=SNP observed in the dbSNP public database,        “HGBASE”=SNP observed in the HGBASE public database, “HGMD”=SNP        observed in the Human Gene Mutation Database (HGMD) public        database, “HapMap”=SNP observed in the International HapMap        Project public database, “CSNP”=SNP observed in an internal        Applied Biosystems (Foster City, Calif.) database of coding SNPS        (cSNPs)) (NOTE: multiple “Applera” source entries for a single        SNP indicate that the same SNP was covered by multiple        overlapping amplification products and the re-sequencing results        (e.g., observed allele counts) from each of these amplification        products is being provided).

For the following SNPs provided in Table 1 and/or 2, the SNP sourcefalls into one of the following three categories: 1) SNPs for which theSNP source is only “Applera” and none other, 2) SNPs for which the SNPsource is only “Celera Diagnostics” and none other, and 3) SNPs forwhich the SNP source is both “Applera” and “Celera Diagnostics” but noneother (the hCV identification number and SEQ ID NO for the SNP's genomiccontext sequence in Table 2 are indicated): hCV22275299 (SEQ ID NO:482),hCV25615822 (SEQ ID NO:639), hCV25651109 (SEQ ID NO:840), hCV25951678(SEQ ID NO:1013), and hCV25615822 (SEQ ID NO:1375). These SNPs have notbeen observed in any of the public databases (dbSNP, HGBASE, and HGMD),and were also not observed during shotgun sequencing and assembly of theCelera human genome sequence (i.e., “Celera” SNP source).

-   -   Population/allele/allele count information in the format of        [population1(first_allele,count1second_allele,count)population2(first_allele,count1second_allele,count)        total (first_allele,total count|second_allele,total count)]. The        information in this field includes populations/ethnic groups in        which particular SNP alleles have been observed        (“cau”=Caucasian, “his”=Hispanic, “chn”=Chinese, and        “afr”=African-American, “jpn”=Japanese, “ind”=Indian,        “mex”=Mexican, “ain”=“American Indian, “cra”=Celera donor,        “no_pop”=no population information available), identified SNP        alleles, and observed allele counts (within each population        group and total allele counts), where available [“-” in the        allele field represents a deletion allele of an        insertion/deletion (“indel”) polymorphism (in which case the        corresponding insertion allele, which may be comprised of one or        more nucleotides, is indicated in the allele field on the        opposite side of the “I”); “-” in the count field indicates that        allele count information is not available]. For certain SNPs        from the public dbSNP database, population/ethnic information is        indicated as follows (this population information is publicly        available in dbSNP): “HISP1”=human individual DNA (anonymized        samples) from 23 individuals of self-described HISPANIC        heritage; “PAC1”=human individual DNA (anonymized samples) from        24 individuals of self-described PACIFIC RIM heritage;        “CAUC1”=human individual DNA (anonymized samples) from 31        individuals of self-described CAUCASIAN heritage; “AFR1”=human        individual DNA (anonymized samples) from 24 individuals of        self-described AFRICAN/AFRICAN AMERICAN heritage; “P1”=human        individual DNA (anonymized samples) from 102 individuals of        self-described heritage; “PA130299515”; “SC_12_A”=SANGER 12 DNAs        of Asian origin from Corielle cell repositories, 6 of which are        male and 6 female; “SC_12_C”=SANGER 12 DNAs of Caucasian origin        from Corielle cell repositories from the CEPH/UTAH library. Six        male and 6 female; “SC_12_AA”=SANGER 12 DNAs of African-American        origin from Corielle cell repositories 6 of which are male and 6        female; “SC_95_C”=SANGER 95 DNAs of Caucasian origin from        Corielle cell repositories from the CEPH/UTAH library; and        “SC_12_CA”=Caucasians—12 DNAs from Corielle cell repositories        that are from the CEPH/UTAH library (six male and six female).

NOTE: For SNPs of “Applera” SNP source, genes/regulatory regions of 39individuals (20 Caucasians and 19 African Americans) were re-sequencedand, since each SNP position is represented by two chromosomes in eachindividual (with the exception of SNPs on X and Y chromosomes in males,for which each SNP position is represented by a single chromosome), upto 78 chromosomes were genotyped for each SNP position. Thus, the sum ofthe African-American (“afr”) allele counts is up to 38, the sum of theCaucasian allele counts (“cau”) is up to 40, and the total sum of allallele counts is up to 78.

(NOTE: semicolons separate population/allele/count informationcorresponding to each indicated SNP source; i.e., if four SNP sourcesare indicated, such as “Celera”, “dbSNP”, “HGBASE”, and “HGMD”, thenpopulation/allele/count information is provided in four groups which areseparated by semicolons and listed in the same order as the listing ofSNP sources, with each population/allele/count information groupcorresponding to the respective SNP source based on order; thus, in thisexample, the first population/allele/count information group wouldcorrespond to the first listed SNP source (Celera) and the thirdpopulation/allele/count information group separated by semicolons wouldcorrespond to the third listed SNP source (HGBASE); ifpopulation/allele/count information is not available for any particularSNP source, then a pair of semicolons is still inserted as aplace-holder in order to maintain correspondence between the list of SNPsources and the corresponding listing of population/allele/countinformation)

-   -   SNP type (e.g., location within gene/transcript and/or predicted        functional effect) [“MIS-SENSE MUTATION”=SNP causes a change in        the encoded amino acid (i.e., a non-synonymous coding SNP);        “SILENT MUTATION”=SNP does not cause a change in the encoded        amino acid (i.e., a synonymous coding SNP); “STOP CODON        MUTATION”=SNP is located in a stop codon; “NONSENSE        MUTATION”=SNP creates or destroys a stop codon; “UTR 5”=SNP is        located in a 5′ UTR of a transcript; “UTR 3”=SNP is located in a        3′ UTR of a transcript; “PUTATIVE UTR 5”=SNP is located in a        putative 5′ UTR; “PUTATIVE UTR 3”=SNP is located in a putative        3′ UTR; “DONOR SPLICE SITE”=SNP is located in a donor splice        site (5′ intron boundary); “ACCEPTOR SPLICE SITE”=SNP is located        in an acceptor splice site (3′ intron boundary); “CODING        REGION”=SNP is located in a protein-coding region of the        transcript; “EXON”=SNP is located in an exon; “INTRON”=SNP is        located in an intron; “hmCS”=SNP is located in a human-mouse        conserved segment; “TFBS”=SNP is located in a transcription        factor binding site; “UNKNOWN”=SNP type is not defined;        “INTERGENIC”=SNP is intergenic, i.e., outside of any gene        boundary]    -   Protein coding information (Table 1 only), where relevant, in        the format of [protein SEQ ID NO:#, amino acid position, (amino        acid-1, codon1) (amino acid-2, codon2)]. The information in this        field includes SEQ ID NO of the encoded protein sequence,        position of the amino acid residue within the protein identified        by the SEQ ID NO that is encoded by the codon containing the        SNP, amino acids (represented by one-letter amino acid codes)        that are encoded by the alternative SNP alleles (in the case of        stop codons, “X” is used for the one-letter amino acid code),        and alternative codons containing the alternative SNP        nucleotides which encode the amino acid residues (thus, for        example, for missense mutation-type SNPs, at least two different        amino acids and at least two different codons are generally        indicated; for silent mutation-type SNPs, one amino acid and at        least two different codons are generally indicated, etc.). In        instances where the SNP is located outside of a protein-coding        region (e.g., in a UTR region), “None” is indicated following        the protein SEQ ID NO.

Description of Table 3

Table 3 provides sequences (SEQ ID NOS:1567-1914) of exemplary primersthat can be used to assay certain SNPs by allele-specific PCR, such asfor stroke-related uses.

Table 3 provides the following:

-   -   the column labeled “Marker” provides an hCV identification        number for each SNP that can be detected using the corresponding        primers.    -   the column labeled “Alleles” designates the two alternative        alleles (i.e., nucleotides) at the SNP site. These alleles are        targeted by the allele-specific primers (the allele-specific        primers are shown as Primer 1 and Primer 2). Note that alleles        may be presented in Table 3 based on a different orientation        (i.e., the reverse complement) relative to how the same alleles        are presented in Tables 1-2.    -   the column labeled “Primer 1 (Allele-Specific Primer)” provides        an allele-specific primer that is specific for an allele        designated in the “Alleles” column.    -   the column labeled “Primer 2 (Allele-Specific Primer)” provides        an allele-specific primer that is specific for the other allele        designated in the “Alleles” column.    -   the column labeled “Common Primer” provides a common primer that        is used in conjunction with each of the allele-specific primers        (i.e., Primer 1 and Primer 2) and which hybridizes at a site        away from the SNP position.

All primer sequences are given in the 5′ to 3′ direction.

Each of the nucleotides designated in the “Alleles” column matches or isthe reverse complement of (depending on the orientation of the primerrelative to the designated allele) the 3′ nucleotide of theallele-specific primer (i.e., either Primer 1 or Primer 2) that isspecific for that allele.

Description of Table 4

Table 4 provides a list of LD SNPs that are related to and derived fromcertain interrogated SNPs. The interrogated SNPs, which are shown incolumn 1 (which indicates the hCV identification numbers of eachinterrogated SNP) and column 2 (which indicates the public rsidentification numbers of each interrogated SNP) of Table 4, arestatistically significantly associated with stroke as shown in thetables. These LD SNPs are provided as an example of SNPs which can alsoserve as markers for disease association based on their being in LD withan interrogated SNP. The criteria and process of selecting such LD SNPs,including the calculation of the r² value and the r² threshold value,are described in Example Eight, below.

In Table 4, the column labeled “Interrogated SNP” presents each markeras identified by its unique hCV identification number. The columnlabeled “Interrogated rs” presents the publicly known identifier rsnumber for the corresponding hCV number. The column labeled “LD SNP”presents the hCV numbers of the LD SNPs that are derived from theircorresponding interrogated SNPs. The column labeled “LD SNP rs” presentsthe publicly known rs number for the corresponding hCV number. Thecolumn labeled “Power” presents the level of power where the r²threshold is set. For example, when power is set at 0.51, the thresholdr² value calculated therefrom is the minimum r² that an LD SNP must havein reference to an interrogated SNP, in order for the LD SNP to beclassified as a marker capable of being associated with a diseasephenotype at greater than 51% probability. The column labeled “Thresholdr²” presents the minimum value of r² that an LD SNP must meet inreference to an interrogated SNP in order to qualify as an LD SNP. Thecolumn labeled “r²” presents the actual r² value of the LD SNP inreference to the interrogated SNP to which it is related.

Description of Tables 5-38

Table 5 provides baseline characteristics of ARIC participants in theischemic stroke study.

Table 6 provides SNPs associated with incident ischemic stroke in theARIC study.

See Example One for further information relating to Tables 5-6.

Tables 7, 8, and 9 provide SNPs, identified from among the 51 SNPsanalyzed in ARIC participants, that predict ischemic stroke risk thatwere identified by Cox proportional hazard analysis as each having atwo-sided p-value of <0.2 after adjusting for age and sex and also ahazard ratio (HRR)>1.0 in whites (Table 7), blacks (Table 8), and bothwhites and blacks (Table 9) (the p-values shown in Tables 7-9 aretwo-sided p-values; thus, the one-sided p-values for these SNPs are halfof these two-sided p-values). See “Supplemental Analysis of SNPs in theARIC Study” section for further information relating to Tables 7-9.

Table 10 provides baseline characteristics of CHS participants in theischemic stroke study.

Table 11 provides SNPs associated with incident ischemic stroke in whiteparticipants of CHS.

Table 12 provides SNPs associated with incident ischemic stroke inAfrican American participants of CHS.

Table 13 shows that Val allele homozygotes of ABCG2 Val12Met, comparedwith the Met allele carriers, are associated with increased risk ofincident ischemic stroke in both white and African American Participantsof CHS.

See Example Two for further information relating to Tables 10-13.

Table 14 provides three SNPs that predict ischemic stroke risk that wereidentified by Cox proportional hazard analysis as each having one-sidedp-values of <=0.05 in whites after adjusting for age and sex, and alsoafter adjusting for traditional risk factors. See “Supplemental Analysisof SNPs in the CHS Study” section for further information relating toTable 14.

Table 15 provides characteristics of noncardioembolic stroke cases andhealthy controls in the Vienna Stroke Registry (VSR) study.

Table 16 provides characteristics of six SNPs tested for associationwith noncardioembolic stroke in VSR.

Table 17 provides results of analysis for association of six SNPs withnoncardioembolic stroke in VSR. In Table 17, individuals with missinggenotype or traditional risk factor information were excluded from caseand control counts; Model 1 was adjusted for age and sex; Model 2 wasadjusted for age, sex, smoking, hypertension, diabetes, dyslipidemia,and BMI; and “q” is the false discovery rate q value.

See Example Three for further information relating to Tables 15-17.

Table 18 provides SNPs associated (2-sided p-value of <0.2) withischemic stroke (labeled “ischemic” in the “outcome” column),atherothrombotic stroke (labeled “athero” in the “outcome” column),and/or early-onset stroke (labeled “early-onset” in the “outcome”column) in the VSR study either before or after adjustment fortraditional risk factors (results after adjustment are labeled “yes” andresults before adjustment are labeled “no” in the “adjust?” column) (thep-values shown in Table 18 are two-sided p-values; thus, the one-sidedp-values for these SNPs are half of these two-sided p-values). See“Supplemental Analysis of SNPs in the Vienna Stroke Registry” sectionfor further information relating to Table 18.

Table 19 (provided as Tables 19A-C to reduce the table width, thus theorder of the rows corresponds to the same markers and studies acrosseach of Tables 19A-C) provides 61 SNPs that were associated with strokerisk in the UCSF/CCF study (1-sided p<0.05 or 2-sided p<0.1) and had thesame risk allele as in the VSR study. Table 19 provides the strokeassociation data in both the UCSF/CCF and the VSR studies. In Table 19A,the column labeled “RefAllele” refers to the major allele and the columnlabeled “Allele” refers to the alternative (minor) allele. Where the“OR” (in Table 19C) is greater than one, carrying the minor allele hasgreater stroke risk compared to carrying the major (reference) allele,so the minor allele would be the risk allele. Where the “OR” (in Table19C) is less than one, the major allele would be the risk allele. SeeExample Four below for further information relating to Table 19.

Tables 20-21 provide SNPs that showed significant association withstroke risk in the German West Study (which may be interchangeablyreferred to herein as the “Muenster” Stroke Study). Table 20 providesSNPs associated with stroke risk that have the same risk allele and2-sided p-values that are less than 0.1 (equivalent to 1-sided p-valuesthat are less than 0.05), and Table 21 provides SNPs associated withstroke risk that have the same risk allele and 2-sided p-values that arebetween 0.1 and 0.2 (equivalent to 1-sided p-values that are between0.05 and 0.1). In Tables 20-21, the following abbreviations are used forthe endpoints in the column labeled “outcome”: “ischemic_stk”=ischemicstroke, “nonce_stk”=noncardioembolic stroke (ischemic strokes that werenot cardioembolic in origin), “CE_stk”=cardioembolic stroke,“athero_stk”=atherothrombotic stroke, “lacunar_stk”=Lacunar stroke,“nohd_stk”=no heart disease stroke (ischemic stroke cases excludingthose with a history of heart disease), “recurrent_stk”=recurrent stroke(stroke cases that also had a prior history of stroke), and“EO_stk”=early onset stroke (cases that are younger than the median ageof all cases, and controls that were older than the median age of allcontrols). See Example Five below for further information relating toTables 20-21.

Tables 22-32 and 37-38 provide SNPs associated with stroke risk orstroke statin response (SSR) in two pravastatin trials: CARE(“Cholesterol and Recurrent Events” study, which is comprised ofindividuals who have had an MI) and PROSPER (“Prospective Study ofPravastatin in the Elderly at Risk” study, which is comprised of elderlyindividuals with or without a history of cardiovascular disease). SNPsthat were significantly associated with stroke risk in CARE are providedin Tables 22, 24, and 26. SNPs that were significantly associated withSSR in CARE are provided in Tables 23, 25, and 27. Results of theanalysis of the MYH15 SNP (rs3900940/hcv7425232) for association withstroke risk in CARE are provided in Table 28. SNPs that weresignificantly associated with stroke risk in PROSPER are provided inTable 29 (which lists SNPs having P_all<0.2, which is the p-value basedon the entire study cohort) and Table 30 (which lists SNPs havingP_placebo<0.2, which is the p-value based on just the placebo group).SNPs that were significantly associated with SSR in PROSPER are providedin Table 31 (which lists SNPs having P_(int)<0.1) and Table 32 (whichlists SNPs having P_(int)<0.2), which provide results of analyses ofpravastatin-treated versus placebo-treated individuals. Tables 37-38provide the results of further analyses of the chromosome 9p21 SNPrs10757274 (hCV26505812) for association with SSR in CARE (Table 37) andPROSPER (Table 38), including both unadjusted and adjusted analyses(adjusted for factors such as age, gender, smoking status, hypertension,diabetes, BMI, and LDL and HDL levels). Table 37 provides results inCARE, and Table 38 provides results in PROSPER (whether each analysis isunadjusted or adjusted is indicated in the “adjust” column in Table 37,or by “unadj” and “adj” column labels in Tables 38).

With respect to Tables 22-32 and 37-38, the columns labeled “Genotype”(in Tables 22-28 and 37), “Geno_Placebo” (in Tables 29-30 and 38), and“Geno_Resp” (in Tables 31-32 and 38) indicate the genotype which thegiven stroke risk or SSR results correspond to. All the p-values(including P_(int) values) provided in Tables 22-32 and 37-38 aretwo-sided p-values (two-sided p-value cutoffs of 0.1 and 0.2 areequivalent to one-sided p-value cutoffs of 0.05 and 0.1, respectively).In Tables 23, 25, 27, 31-32, and 37-38 (which include results pertainingto SSR), the p-value (which is labeled “p-value” in Tables 23, 25, 27,and 37, and labeled “p_resp” in Tables 31-32 and 38) refers to thesignificance of the statin benefit (i.e., the HR of pravastatin-treatedversus placebo-treated carriers of a given genotype), whereas theP_(int) value (which is labeled as “pval_intx” in Tables 23, 25, 27, and37, and labeled “p_int_resp” in Tables 31-32 and 38) refers to thesignificance of the genotype by treatment interaction, i.e., thesignificance of the difference in statin response among three groupsdefined by the three genotypes (homozygotes of each of the twoalternative alleles, plus heterozygotes, as indicated in the columnlabeled “Genotype” or “Geno”) or two groups defined by the carriers andnoncarriers of one or the other allele (“Dom” or “Rec”, as indicated inthe column labeled “Mode”). In Tables 29-32 and 38, the columns labeled“LOWER_PLACEBO” and “UPPER_PLACEBO” (Tables 29-30 and 38), and“LOWER_RESP” and “UPPER_RESP” (Tables 31-32 and 38), refer to the lowerand upper 95% confidence intervals for the hazard ratios. See ExampleSix below for further information relating to Tables 22-32 and 37-38.

Tables 33-36 provide SNPs that showed significant association withstroke risk in the Cardiovascular Health Study (CHS). Specifically, SNPsthat are associated with stroke risk in white or black individuals with2-sided p-values less than 0.1 (equivalent to 1-sided p-values less than0.05) are provided in Table 33 (white individuals) and Table 34 (blackindividuals), and SNPs that are associated with stroke risk in white orblack individuals with 2-sided p-values between 0.1 and 0.2 (equivalentto 1-sided p-values between 0.05 and 0.1) are provided in Table 35(white individuals) and Table 36 (black individuals). Association wasanalyzed for three related stroke end points, which are indicated inTables 33-36 by the following abbreviations in the column labeled“endpt”: “stroke”=stroke (all subtypes), “ischem”=ischemic stroke(excludes hemorrhagic stroke), and “athero”=atherothrombotic stroke(excludes hemorrhagic stroke and cardioembolic stroke). See ExampleSeven below for further information relating to Tables 33-36.

In the tables, the following abbreviations may be used:“ProbChiSq”=p-value, “PVALUE_2DF” or “2DF P-VALUE”=p-value with twodegrees of freedom, “PVAL_INTX” or “P_INT_RESP”=P_(int) (thesignificance of the genotype by treatment interaction—see description ofTables 23, 25, 27, 31-32, and 37-38 above), “std.ln(OR)”=the standarddeviation of the natural log of the OR, “Hom”=homozygotes,“Het”=heterozygotes, “cnt”=count, “frq”=frequency, “dom”=dominant,“rec”=recessive, “gen”=genotypic, “add”=additive, “HW”=Hardy-Weinberg,“TIA”=transient ischemic stroke (also known as a mini stroke),“events”=number of strokes (including TIA) in the study cohort, “DIAB”,“DIABADA”, or “DIABETES_1”=diabetes, “HTN” or “HYPERTEN_1”=hypertension,“ENDPT4F1”=endpoint of stroke or TIA (official endpoint of the CAREStudy), “TIMEVAR”=length of time from baseline to the time ofevent/endpoint, “TIMETO_EP4F1”=length of time from baseline to the timeof endpoint ENDPT4F1 (stroke or TIA), “TRF”=traditional risk factors,“BMI”=body mass index, “AGEBL”=age, “GEND01”=gender, “PRESSM” or“CURRSMK”=smoking status, “LDLADJBL” or “BASE_LDL”=low-densitylipoprotein (LDL) cholesterol, and “HDL44BL” or “BASE_HDL”=high-densitylipoprotein (HDL) cholesterol (“BASE_LDL” and “BASE_HDL” adjustments arebased on continuous variables rather than discrete cutoffs). Two-“sided”p-values may be interchangeably referred to as two-“tailed” p-values.

Throughout the tables, “HR” or “HRR” refers to the hazard ratio, “OR”refers to the odds ratio, terms such as “90% CI” or “95% CI” refer tothe 90% or 95% confidence interval (respectively) for the hazard ratioor odds ratio (“CI”/“confidence interval” and “CL”/“confidence limit”may be used herein interchangeably), and terms such as “OR99CI.L” and“OR99CI.U” refer to the lower and upper 99% confidence intervals(respectively) for the odds ratio. Hazard ratios (“HR” or “HRR”) or oddsratios (OR) that are greater than one indicate that a given allele (orcombination of alleles such as a haplotype, diplotype, or two-locusdiplotype) is a risk allele (which may also be referred to as asusceptibility allele), whereas hazard ratios or odds ratios that areless than one indicate that a given allele is a non-risk allele (whichmay also be referred to as a protective allele). For a given riskallele, the other alternative allele at the SNP position (which can bederived from the information provided in Tables 1-2, for example) may beconsidered a non-risk allele. For a given non-risk allele, the otheralternative allele at the SNP position may be considered a risk allele.

Thus, with respect to disease risk (e.g., stroke), if the risk estimate(odds ratio or hazard ratio) for a particular allele at a SNP positionis greater than one, this indicates that an individual with thisparticular allele has a higher risk for the disease than an individualwho has the other allele at the SNP position. In contrast, if the riskestimate (odds ratio or hazard ratio) for a particular allele is lessthan one, this indicates that an individual with this particular allelehas a reduced risk for the disease compared with an individual who hasthe other allele at the SNP position.

With respect to drug response (e.g., response to a statin), if the riskestimate (odds ratio or hazard ratio) of those treated with pravastatincompared with those treated with a placebo within a particular genotypeis less than one, this indicates that an individual with this particulargenotype would benefit from the drug (an odds ratio or hazard ratioequal to one would indicate that the drug has no effect). As usedherein, the term “benefit” (with respect to a preventive or therapeuticdrug treatment) is defined as achieving a reduced risk for a diseasethat the drug is intended to treat or prevent (e.g., stroke) byadministrating the drug treatment, compared with the risk for thedisease in the absence of receiving the drug treatment (or receiving aplacebo in lieu of the drug treatment) for the same genotype. The term“benefit” may be used herein interchangeably with terms such as “respondpositively” or “positively respond”.

For stroke risk and statin response associations based on samples fromthe CARE and PROSPER trials described herein, stroke risk is assessed bycomparing the risk of stroke for a given genotype with the risk ofstroke for a reference genotype either in the placebo arm of the trialor in the whole study population of the trial, and statin response isassessed by comparing the risk of stroke in the pravastatin arm of thetrial with the risk of stroke in the placebo arm of the trial for thesame genotype.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1a-1b show a comparison of Kaplan-Meier estimates of thecumulative incidence of ischemic stroke among Val allele homozygotes ofthe ABCG2 Val12Met SNP (rs2231137/hCV15854171) and among Met allelecarriers in white (FIG. 1a ) and in African American (FIG. 1b )participants of CHS (see Example Two).

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS OF THE INVENTION

The present invention provides SNPs associated with stroke risk, andSNPs that are associated with an individual's responsiveness totherapeutic agents, particularly statins, which may be used for thetreatment (including preventive treatment) of stroke. The presentinvention further provides nucleic acid molecules containing SNPs,methods and reagents for the detection of the SNPs disclosed herein,uses of these SNPs for the development of detection reagents, and assaysor kits that utilize such reagents. The SNPs disclosed herein are usefulfor diagnosing, prognosing, screening for, and evaluating predispositionto stroke and related pathologies in humans. The drugresponse-associated SNPs disclosed herein are particularly useful forpredicting, screening for, and evaluating response to statin treatment,particularly treatment or prevention of stroke using statins, in humans.Furthermore, such SNPs and their encoded products are useful targets forthe development of therapeutic and preventive agents.

A large number of SNPs have been identified from re-sequencing DNA from39 individuals, and they are indicated as “Applera” SNP source in Tables1-2. Their allele frequencies observed in each of the Caucasian andAfrican-American ethnic groups are provided. Additional SNPs includedherein were previously identified during shotgun sequencing and assemblyof the human genome, and they are indicated as “Celera” SNP source inTables 1-2. Furthermore, the information provided in Table 1-2,particularly the allele frequency information obtained from 39individuals and the identification of the precise position of each SNPwithin each gene/transcript, allows haplotypes (i.e., groups of SNPsthat are co-inherited) to be readily inferred. The present inventionencompasses SNP haplotypes, as well as individual SNPs.

Thus, the present invention provides individual SNPs associated withstroke, and/or drug response (particularly statin response), as well ascombinations of SNPs and haplotypes in genetic regions associated withstroke, polymorphic/variant transcript sequences (SEQ ID NOS:1-80) andgenomic sequences (SEQ ID NOS:260-435) containing SNPs, encoded aminoacid sequences (SEQ ID NOS: 81-160), and both transcript-based SNPcontext sequences (SEQ ID NOS:161-259) and genomic-based SNP contextsequences (SEQ ID NOS:436-1566) (transcript sequences, proteinsequences, and transcript-based SNP context sequences are provided inTable 1 and the Sequence Listing; genomic sequences and genomic-basedSNP context sequences are provided in Table 2 and the Sequence Listing),methods of detecting these polymorphisms in a test sample, methods ofdetermining the risk of an individual of having a stroke, methods ofdetermining if an individual is likely to respond to a particulartreatment such as statins (particularly for treating or preventingstroke), methods of screening for compounds useful for treatingdisorders associated with a variant gene/protein such as stroke,compounds identified by these screening methods, methods of using thedisclosed SNPs to select a treatment/preventive strategy or therapeuticagent (e.g., a statin), methods of treating or preventing a disorderassociated with a variant gene/protein, and methods of using the SNPs ofthe present invention for human identification.

For example, certain embodiments provide methods of using any ofrs3900940/hCV7425232 (MYH15), rs3814843/hCV11476411 (CALM1),rs2200733/hCV16158671 (chromosome 4q25), and/or rs10757274/hCV26505812(chromosome 9p21) for determining stroke risk in an individual, andmethods of using rs10757274/hCV26505812 (chromosome 9p21) fordetermining whether an individual will benefit from statin treatment.

Since vascular disorders/diseases share certain similar features thatmay be due to common genetic factors that are involved in theirunderlying mechanisms, the SNPs identified herein as being particularlyassociated with stroke may be used as diagnostic/prognostic markers ortherapeutic targets for other vascular diseases such as coronary heartdisease (CHD), atherosclerosis, cardiovascular disease, congestive heartfailure, congenital heart disease, and pathologies and symptomsassociated with various heart diseases (e.g., angina, hypertension), aswell as for predicting responses to drugs such as statins that are usedto treat cardiovascular diseases.

The present invention further provides methods for selecting orformulating a treatment regimen (e.g., methods for determining whetheror not to administer statin treatment to an individual who haspreviously had a stroke, or who is at risk for having a stroke in thefuture, methods for selecting a particular statin-based treatmentregimen such as dosage and frequency of administration of statin, or aparticular form/type of statin such as a particular pharmaceuticalformulation or statin compound, methods for administering analternative, non-statin-based treatment to individuals who are predictedto be unlikely to respond positively to statin treatment, etc.), andmethods for determining the likelihood of experiencing toxicity or otherundesirable side effects from statin treatment, etc. The presentinvention also provides methods for selecting individuals to whom astatin or other therapeutic will be administered based on theindividual's genotype, and methods for selecting individuals for aclinical trial of a statin or other therapeutic agent based on thegenotypes of the individuals (e.g., selecting individuals to participatein the trial who are most likely to respond positively from the statintreatment and/or excluding individuals from the trial who are unlikelyto respond positively from the statin treatment).

The present invention provides novel SNPs associated with stroke andrelated pathologies, as well as SNPs that were previously known in theart, but were not previously known to be associated with stroke orresponse to statin treatment. Accordingly, the present inventionprovides novel compositions and methods based on the novel SNPsdisclosed herein, and also provides novel methods of using the known,but previously unassociated, SNPs in methods relating to evaluating anindividual's likelihood of having a first or recurrent stroke,prognosing the severity of stroke in an individual, or prognosing anindividual's recovery from stroke, and methods relating to evaluating anindividual's likelihood of responding to statin treatment (particularlystatin treatment, including preventive treatment, of stroke). In Tables1-2, known SNPs are identified based on the public database in whichthey have been observed, which is indicated as one or more of thefollowing SNP types: “dbSNP”=SNP observed in dbSNP, “HGBASE”=SNPobserved in HGBASE, and “HGMD”=SNP observed in the Human Gene MutationDatabase (HGMD).

Particular SNP alleles of the present invention can be associated witheither an increased risk of having a stroke (or related pathologies), ora decreased risk of having a stroke. SNP alleles that are associatedwith a decreased risk of having a stroke may be referred to as“protective” alleles, and SNP alleles that are associated with anincreased risk of having a stroke may be referred to as “susceptibility”alleles, “risk” alleles, or “risk factors”. Thus, whereas certain SNPs(or their encoded products) can be assayed to determine whether anindividual possesses a SNP allele that is indicative of an increasedrisk of having a stroke (i.e., a susceptibility allele), other SNPs (ortheir encoded products) can be assayed to determine whether anindividual possesses a SNP allele that is indicative of a decreased riskof having a stroke (i.e., a protective allele). Similarly, particularSNP alleles of the present invention can be associated with either anincreased or decreased likelihood of responding to a particulartreatment or therapeutic compound (e.g., statins), or an increased ordecreased likelihood of experiencing toxic effects from a particulartreatment or therapeutic compound. The term “altered” may be used hereinto encompass either of these two possibilities (e.g., an increased or adecreased risk/likelihood).

Those skilled in the art will readily recognize that nucleic acidmolecules may be double-stranded molecules and that reference to aparticular site on one strand refers, as well, to the corresponding siteon a complementary strand. In defining a SNP position, SNP allele, ornucleotide sequence, reference to an adenine, a thymine (uridine), acytosine, or a guanine at a particular site on one strand of a nucleicacid molecule also defines the thymine (uridine), adenine, guanine, orcytosine (respectively) at the corresponding site on a complementarystrand of the nucleic acid molecule. Thus, reference may be made toeither strand in order to refer to a particular SNP position, SNPallele, or nucleotide sequence. Probes and primers, may be designed tohybridize to either strand and SNP genotyping methods disclosed hereinmay generally target either strand. Throughout the specification, inidentifying a SNP position, reference is generally made to theprotein-encoding strand, only for the purpose of convenience.

References to variant peptides, polypeptides, or proteins of the presentinvention include peptides, polypeptides, proteins, or fragmentsthereof, that contain at least one amino acid residue that differs fromthe corresponding amino acid sequence of the art-knownpeptide/polypeptide/protein (the art-known protein may beinterchangeably referred to as the “wild-type”, “reference”, or “normal”protein). Such variant peptides/polypeptides/proteins can result from acodon change caused by a nonsynonymous nucleotide substitution at aprotein-coding SNP position (i.e., a missense mutation) disclosed by thepresent invention. Variant peptides/polypeptides/proteins of the presentinvention can also result from a nonsense mutation, i.e., a SNP thatcreates a premature stop codon, a SNP that generates a read-throughmutation by abolishing a stop codon, or due to any SNP disclosed by thepresent invention that otherwise alters the structure,function/activity, or expression of a protein, such as a SNP in aregulatory region (e.g. a promoter or enhancer) or a SNP that leads toalternative or defective splicing, such as a SNP in an intron or a SNPat an exon/intron boundary. As used herein, the terms “polypeptide”,“peptide”, and “protein” are used interchangeably.

As used herein, an “allele” may refer to a nucleotide at a SNP position(wherein at least two alternative nucleotides are present in thepopulation at the SNP position, in accordance with the inherentdefinition of a SNP) or may refer to an amino acid residue that isencoded by the codon which contains the SNP position (where thealternative nucleotides that are present in the population at the SNPposition form alternative codons that encode different amino acidresidues). An “allele” may also be referred to herein as a “variant”.Also, an amino acid residue that is encoded by a codon containing aparticular SNP may simply be referred to as being encoded by the SNP.

A phrase such as “as represented by”, “as shown by”, “as symbolized by”,or “as designated by” may be used herein to refer to a SNP within asequence (e.g., a polynucleotide context sequence surrounding a SNP),such as in the context of “a polymorphism as represented by position 101of SEQ ID NO:X or its complement”. Typically, the sequence surrounding aSNP may be recited when referring to a SNP, however the sequence is notintended as a structural limitation beyond the specific SNP positionitself. Rather, the sequence is recited merely as a way of referring tothe SNP (in this example, “SEQ ID NO:X or its complement” is recited inorder to refer to the SNP located at position 101 of SEQ ID NO:X, butSEQ ID NO:X or its complement is not intended as a structural limitationbeyond the specific SNP position itself). A SNP is a variation at asingle nucleotide position and therefore it is customary to refer tocontext sequence (e.g., SEQ ID NO:X in this example) surrounding aparticular SNP position in order to uniquely identify and refer to theSNP. Alternatively, a SNP can be referred to by a unique identificationnumber such as a public “rs” identification number or an internal “hCV”identification number, such as provided herein for each SNP (e.g., inTables 1-2).

With respect to an individual's risk for a disease or predicted drugresponsiveness (e.g., based on the presence or absence of one or moreSNPs disclosed herein in the individual's nucleic acid), terms such as“assigning” or “designating” may be used herein to characterize theindividual's risk for the disease.

As used herein, the term “benefit” (with respect to a preventive ortherapeutic drug treatment) is defined as achieving a reduced risk for adisease that the drug is intended to treat or prevent (e.g., stroke) byadministrating the drug treatment (e.g., a statin), compared with therisk for the disease in the absence of receiving the drug treatment (orreceiving a placebo in lieu of the drug treatment) for the samegenotype. The term “benefit” may be used herein interchangeably withterms such as “respond positively” or “positively respond”.

As used herein, the terms “drug” and “therapeutic agent” are usedinterchangeably, and may include, but are not limited to, small moleculecompounds, biologics (e.g., antibodies, proteins, protein fragments,fusion proteins, glycoproteins, etc.), nucleic acid agents (e.g.,antisense, RNAi/siRNA, and microRNA molecules, etc.), vaccines, etc.,which may be used for therapeutic and/or preventive treatment of adisease (e.g., stroke).

The statin response-associated SNPs disclosed herein are useful withrespect to any statin (HMG-CoA reductase inhibitor), including but notlimited to pravastatin (Pravachol®), atorvastatin (Lipitor®),storvastatin, rosuvastatin (Crestor®), fluvastatin (Lescol®), lovastatin(Mevacor®), and simvastatin (Zocor®), as well as combination therapiesthat include a statin such as simvastatin+ezetimibe (Vytorin®),lovastatin+niacin extended-release (Advicor®), andatorvastatin+amlodipine besylate (Caduet®).

Furthermore, the drug response-associated SNPs disclosed herein may alsobe used for predicting an individual's responsiveness to drugs otherthan statins that are used to treat or prevent stroke, and these SNPsmay also be used for predicting an individual's responsiveness tostatins for the treatment or prevention of disorders other than stroke,particularly cancer. For example, the use of statins in the treatment ofcancer is reviewed in: Hindler et al., “The role of statins in cancertherapy”, Oncologist. 2006 March; 11(3):306-15; Demierre et al.,“Statins and cancer prevention”, Nat Rev Cancer. 2005 December;5(12):930-42; Stamm et al., “The role of statins in cancer preventionand treatment”, Oncology. 2005 May; 19(6):739-50; and Sleijfer et al.,“The potential of statins as part of anti-cancer treatment”, Eur JCancer. 2005 March; 41(4):516-22, each of which is incorporated hereinby reference in their entirety.

Drug response with respect to statins may be referred to herein as“stroke statin response” or “SSR”.

The various methods described herein, such as correlating the presenceor absence of a polymorphism with an altered (e.g., increased ordecreased) risk (or no altered risk) for stroke (and/or correlating thepresence or absence of a polymorphism with the predicted response of anindividual to a drug such as a statin), can be carried out by automatedmethods such as by using a computer (or other apparatus/devices such asbiomedical devices, laboratory instrumentation, or otherapparatus/devices having a computer processor) programmed to carry outany of the methods described herein. For example, computer software(which may be interchangeably referred to herein as a computer program)can perform the step of correlating the presence or absence of apolymorphism in an individual with an altered (e.g., increased ordecreased) risk (or no altered risk) for stroke for the individual.Computer software can also perform the step of correlating the presenceor absence of a polymorphism in an individual with the predictedresponse of the individual to a therapeutic agent (such as a statin) orother treatment. Accordingly, certain embodiments of the inventionprovide a computer (or other apparatus/device) programmed to carry outany of the methods described herein.

Reports, Programmed Computers, Business Methods, and Systems

The results of a test (e.g., an individual's risk for stroke or anindividual's predicted drug responsiveness such as statin response,based on assaying one or more SNPs disclosed herein, and/or anindividual's allele(s)/genotype at one or more SNPs disclosed herein,etc.), and/or any other information pertaining to a test, may bereferred to herein as a “report”. A tangible report can optionally begenerated as part of a testing process (which may be interchangeablyreferred to herein as “reporting”, or as “providing” a report,“producing” a report, or “generating” a report).

Examples of tangible reports may include, but are not limited to,reports in paper (such as computer-generated printouts of test results)or equivalent formats and reports stored on computer readable medium(such as a CD, USB flash drive or other removable storage device,computer hard drive, or computer network server, etc.). Reports,particularly those stored on computer readable medium, can be part of adatabase, which may optionally be accessible via the internet (such as adatabase of patient records or genetic information stored on a computernetwork server, which may be a “secure database” that has securityfeatures that limit access to the report, such as to allow only thepatient and the patient's medical practitioners to view the report whilepreventing other unauthorized individuals from viewing the report, forexample). In addition to, or as an alternative to, generating a tangiblereport, reports can also be displayed on a computer screen (or thedisplay of another electronic device or instrument).

A report can include, for example, an individual's risk for stroke, ormay just include the allele(s)/genotype that an individual carries atone or more SNPs disclosed herein, which may optionally be linked toinformation regarding the significance of having the allele(s)/genotypeat the SNP (for example, a report on computer readable medium such as anetwork server may include hyperlink(s) to one or more journalpublications or websites that describe the medical/biologicalimplications, such as increased or decreased disease risk, forindividuals having a certain allele/genotype at the SNP). Thus, forexample, the report can include disease risk or other medical/biologicalsignificance (e.g., drug responsiveness, etc.) as well as optionallyalso including the allele/genotype information, or the report may justinclude allele/genotype information without including disease risk orother medical/biological significance (such that an individual viewingthe report can use the allele/genotype information to determine theassociated disease risk or other medical/biological significance from asource outside of the report itself, such as from a medicalpractitioner, publication, website, etc., which may optionally be linkedto the report such as by a hyperlink).

A report can further be “transmitted” or “communicated” (these terms maybe used herein interchangeably), such as to the individual who wastested, a medical practitioner (e.g., a doctor, nurse, clinicallaboratory practitioner, genetic counselor, etc.), a healthcareorganization, a clinical laboratory, and/or any other party or requesterintended to view or possess the report. The act of “transmitting” or“communicating” a report can be by any means known in the art, based onthe format of the report. Furthermore, “transmitting” or “communicating”a report can include delivering a report (“pushing”) and/or retrieving(“pulling”) a report. For example, reports can betransmitted/communicated by various means, including being physicallytransferred between parties (such as for reports in paper format) suchas by being physically delivered from one party to another, or by beingtransmitted electronically or in signal form (e.g., via e-mail or overthe internet, by facsimile, and/or by any wired or wirelesscommunication methods known in the art) such as by being retrieved froma database stored on a computer network server, etc.

In certain exemplary embodiments, the invention provides computers (orother apparatus/devices such as biomedical devices or laboratoryinstrumentation) programmed to carry out the methods described herein.For example, in certain embodiments, the invention provides a computerprogrammed to receive (i.e., as input) the identity (e.g., the allele(s)or genotype at a SNP) of one or more SNPs disclosed herein and provide(i.e., as output) the disease risk (e.g., an individual's risk forstroke) or other result (e.g., disease diagnosis or prognosis, drugresponsiveness, etc.) based on the identity of the SNP(s). Such output(e.g., communication of disease risk, disease diagnosis or prognosis,drug responsiveness, etc.) may be, for example, in the form of a reporton computer readable medium, printed in paper form, and/or displayed ona computer screen or other display.

In various exemplary embodiments, the invention further provides methodsof doing business (with respect to methods of doing business, the terms“individual” and “customer” are used herein interchangeably). Forexample, exemplary methods of doing business can comprise assaying oneor more SNPs disclosed herein and providing a report that includes, forexample, a customer's risk for stroke (based on which allele(s)/genotypeis present at the assayed SNP(s)) and/or that includes theallele(s)/genotype at the assayed SNP(s) which may optionally be linkedto information (e.g., journal publications, websites, etc.) pertainingto disease risk or other biological/medical significance such as bymeans of a hyperlink (the report may be provided, for example, on acomputer network server or other computer readable medium that isinternet-accessible, and the report may be included in a secure databasethat allows the customer to access their report while preventing otherunauthorized individuals from viewing the report), and optionallytransmitting the report. Customers (or another party who is associatedwith the customer, such as the customer's doctor, for example) canrequest/order (e.g., purchase) the test online via the internet (or byphone, mail order, at an outlet/store, etc.), for example, and a kit canbe sent/delivered (or otherwise provided) to the customer (or anotherparty on behalf of the customer, such as the customer's doctor, forexample) for collection of a biological sample from the customer (e.g.,a buccal swab for collecting buccal cells), and the customer (or a partywho collects the customer's biological sample) can submit theirbiological samples for assaying (e.g., to a laboratory or partyassociated with the laboratory such as a party that accepts the customersamples on behalf of the laboratory, a party for whom the laboratory isunder the control of (e.g., the laboratory carries out the assays byrequest of the party or under a contract with the party, for example),and/or a party that receives at least a portion of the customer'spayment for the test). The report (e.g., results of the assay including,for example, the customer's disease risk and/or allele(s)/genotype atthe assayed SNP(s)) may be provided to the customer by, for example, thelaboratory that assays the SNP(s) or a party associated with thelaboratory (e.g., a party that receives at least a portion of thecustomer's payment for the assay, or a party that requests thelaboratory to carry out the assays or that contracts with the laboratoryfor the assays to be carried out) or a doctor or other medicalpractitioner who is associated with (e.g., employed by or having aconsulting or contracting arrangement with) the laboratory or with aparty associated with the laboratory, or the report may be provided to athird party (e.g., a doctor, genetic counselor, hospital, etc.) whichoptionally provides the report to the customer. In further embodiments,the customer may be a doctor or other medical practitioner, or ahospital, laboratory, medical insurance organization, or other medicalorganization that requests/orders (e.g., purchases) tests for thepurposes of having other individuals (e.g., their patients or customers)assayed for one or more SNPs disclosed herein and optionally obtaining areport of the assay results.

In certain exemplary methods of doing business, kits for collecting abiological sample from a customer (e.g., a buccal swab for collectingbuccal cells) are provided (e.g., for sale), such as at an outlet (e.g.,a drug store, pharmacy, general merchandise store, or any otherdesirable outlet), online via the internet, by mail order, etc., wherebycustomers can obtain (e.g., purchase) the kits, collect their ownbiological samples, and submit (e.g., send/deliver via mail) theirsamples to a laboratory which assays the samples for one or more SNPsdisclosed herein (such as to determine the customer's risk for stroke)and optionally provides a report to the customer (of the customer'sdisease risk based on their SNP genotype(s), for example) or providesthe results of the assay to another party (e.g., a doctor, geneticcounselor, hospital, etc.) which optionally provides a report to thecustomer (of the customer's disease risk based on their SNP genotype(s),for example).

Certain further embodiments of the invention provide a system fordetermining an individual's stroke risk, or whether an individual willbenefit from statin treatment (or other therapy) in reducing strokerisk. Certain exemplary systems comprise an integrated “loop” in whichan individual (or their medical practitioner) requests a determinationof such individual's stroke risk (or drug response, etc.), thisdetermination is carried out by testing a sample from the individual,and then the results of this determination are provided back to therequestor. For example, in certain systems, a sample (e.g., blood orbuccal cells) is obtained from an individual for testing (the sample maybe obtained by the individual or, for example, by a medicalpractitioner), the sample is submitted to a laboratory (or otherfacility) for testing (e.g., determining the genotype of one or moreSNPs disclosed herein), and then the results of the testing are sent tothe patient (which optionally can be done by first sending the resultsto an intermediary, such as a medical practitioner, who then provides orotherwise conveys the results to the individual), thereby forming anintegrated loop system for determining an individual's stroke risk (ordrug response, etc.). The portions of the system in which the resultsare transmitted (e.g., between any of a testing facility, a medicalpractitioner, and/or the individual) can be carried out by way ofelectronic or signal transmission (e.g., by computer such as via e-mailor the internet, by providing the results on a website or computernetwork server which may optionally be a secure database, by phone orfax, or by any other wired or wireless transmission methods known in theart).

Isolated Nucleic Acid Molecules and SNP Detection Reagents & Kits

Tables 1 and 2 provide a variety of information about each SNP of thepresent invention that is associated with stroke, including thetranscript sequences (SEQ ID NOS:1-80), genomic sequences (SEQ IDNOS:260-435), and protein sequences (SEQ ID NOS:81-160) of the encodedgene products (with the SNPs indicated by IUB codes in the nucleic acidsequences). In addition, Tables 1 and 2 include SNP context sequences,which generally include 100 nucleotide upstream (5′) plus 100nucleotides downstream (3′) of each SNP position (SEQ ID NOS:161-259correspond to transcript-based SNP context sequences disclosed in Table1, and SEQ ID NOS:436-1566 correspond to genomic-based context sequencesdisclosed in Table 2), the alternative nucleotides (alleles) at each SNPposition, and additional information about the variant where relevant,such as SNP type (coding, missense, splice site, UTR, etc.), humanpopulations in which the SNP was observed, observed allele frequencies,information about the encoded protein, etc.

Isolated Nucleic Acid Molecules

The present invention provides isolated nucleic acid molecules thatcontain one or more SNPs disclosed Table 1 and/or Table 2. Preferredisolated nucleic acid molecules contain one or more SNPs identified asApplera or Celera proprietary. Isolated nucleic acid moleculescontaining one or more SNPs disclosed in at least one of Tables 1-2 maybe interchangeably referred to throughout the present text as“SNP-containing nucleic acid molecules”. Isolated nucleic acid moleculesmay optionally encode a full-length variant protein or fragment thereof.The isolated nucleic acid molecules of the present invention alsoinclude probes and primers (which are described in greater detail belowin the section entitled “SNP Detection Reagents”), which may be used forassaying the disclosed SNPs, and isolated full-length genes,transcripts, cDNA molecules, and fragments thereof, which may be usedfor such purposes as expressing an encoded protein.

As used herein, an “isolated nucleic acid molecule” generally is onethat contains a SNP of the present invention or one that hybridizes tosuch molecule such as a nucleic acid with a complementary sequence, andis separated from most other nucleic acids present in the natural sourceof the nucleic acid molecule. Moreover, an “isolated” nucleic acidmolecule, such as a cDNA molecule containing a SNP of the presentinvention, can be substantially free of other cellular material, orculture medium when produced by recombinant techniques, or chemicalprecursors or other chemicals when chemically synthesized. A nucleicacid molecule can be fused to other coding or regulatory sequences andstill be considered “isolated”. Nucleic acid molecules present innon-human transgenic animals, which do not naturally occur in theanimal, are also considered “isolated”. For example, recombinant DNAmolecules contained in a vector are considered “isolated”. Furtherexamples of “isolated” DNA molecules include recombinant DNA moleculesmaintained in heterologous host cells, and purified (partially orsubstantially) DNA molecules in solution. Isolated RNA molecules includein vivo or in vitro RNA transcripts of the isolated SNP-containing DNAmolecules of the present invention. Isolated nucleic acid moleculesaccording to the present invention further include such moleculesproduced synthetically.

Generally, an isolated SNP-containing nucleic acid molecule comprisesone or more SNP positions disclosed by the present invention withflanking nucleotide sequences on either side of the SNP positions. Aflanking sequence can include nucleotide residues that are naturallyassociated with the SNP site and/or heterologous nucleotide sequences.Preferably the flanking sequence is up to about 500, 300, 100, 60, 50,30, 25, 20, 15, 10, 8, or 4 nucleotides (or any other length in-between)on either side of a SNP position, or as long as the full-length gene orentire protein-coding sequence (or any portion thereof such as an exon),especially if the SNP-containing nucleic acid molecule is to be used toproduce a protein or protein fragment.

For full-length genes and entire protein-coding sequences, a SNPflanking sequence can be, for example, up to about 5 KB, 4 KB, 3 KB, 2KB, 1 KB on either side of the SNP. Furthermore, in such instances, theisolated nucleic acid molecule comprises exonic sequences (includingprotein-coding and/or non-coding exonic sequences), but may also includeintronic sequences. Thus, any protein coding sequence may be eithercontiguous or separated by introns. The important point is that thenucleic acid is isolated from remote and unimportant flanking sequencesand is of appropriate length such that it can be subjected to thespecific manipulations or uses described herein such as recombinantprotein expression, preparation of probes and primers for assaying theSNP position, and other uses specific to the SNP-containing nucleic acidsequences.

An isolated SNP-containing nucleic acid molecule can comprise, forexample, a full-length gene or transcript, such as a gene isolated fromgenomic DNA (e.g., by cloning or PCR amplification), a cDNA molecule, oran mRNA transcript molecule. Polymorphic transcript sequences areprovided in Table 1 and in the Sequence Listing (SEQ ID NOS:1-80), andpolymorphic genomic sequences are provided in Table 2 and in theSequence Listing (SEQ ID NOS:260-435). Furthermore, fragments of suchfull-length genes and transcripts that contain one or more SNPsdisclosed herein are also encompassed by the present invention, and suchfragments may be used, for example, to express any part of a protein,such as a particular functional domain or an antigenic epitope.

Thus, the present invention also encompasses fragments of the nucleicacid sequences provided in Tables 1-2 (transcript sequences are providedin Table 1 as SEQ ID NOS:1-80, genomic sequences are provided in Table 2as SEQ ID NOS:260-435, transcript-based SNP context sequences areprovided in Table 1 as SEQ ID NO:161-259, and genomic-based SNP contextsequences are provided in Table 2 as SEQ ID NO:436-1566) and theircomplements. A fragment typically comprises a contiguous nucleotidesequence at least about 8 or more nucleotides, more preferably at leastabout 12 or more nucleotides, and even more preferably at least about 16or more nucleotides. Further, a fragment could comprise at least about18, 20, 22, 25, 30, 40, 50, 60, 80, 100, 150, 200, 250 or 500 (or anyother number in-between) nucleotides in length. The length of thefragment will be based on its intended use. For example, the fragmentcan encode epitope-bearing regions of a variant peptide or regions of avariant peptide that differ from the normal/wild-type protein, or can beuseful as a polynucleotide probe or primer. Such fragments can beisolated using the nucleotide sequences provided in Table 1 and/or Table2 for the synthesis of a polynucleotide probe. A labeled probe can thenbe used, for example, to screen a cDNA library, genomic DNA library, ormRNA to isolate nucleic acid corresponding to the coding region.Further, primers can be used in amplification reactions, such as forpurposes of assaying one or more SNPs sites or for cloning specificregions of a gene.

An isolated nucleic acid molecule of the present invention furtherencompasses a SNP-containing polynucleotide that is the product of anyone of a variety of nucleic acid amplification methods, which are usedto increase the copy numbers of a polynucleotide of interest in anucleic acid sample. Such amplification methods are well known in theart, and they include but are not limited to, polymerase chain reaction(PCR) (U.S. Pat. Nos. 4,683,195; and 4,683,202; PCR Technology:Principles and Applications for DNA Amplification, ed. H. A. Erlich,Freeman Press, NY, NY, 1992), ligase chain reaction (LCR) (Wu andWallace, Genomics 4:560, 1989; Landegren et al., Science 241:1077,1988), strand displacement amplification (SDA) (U.S. Pat. Nos.5,270,184; and 5,422,252), transcription-mediated amplification (TMA)(U.S. Pat. No. 5,399,491), linked linear amplification (LLA) (U.S. Pat.No. 6,027,923), and the like, and isothermal amplification methods suchas nucleic acid sequence based amplification (NASBA), and self-sustainedsequence replication (Guatelli et al., Proc. Natl. Acad. Sci. USA 87:1874, 1990). Based on such methodologies, a person skilled in the artcan readily design primers in any suitable regions 5′ and 3′ to a SNPdisclosed herein. Such primers may be used to amplify DNA of any lengthso long that it contains the SNP of interest in its sequence.

As used herein, an “amplified polynucleotide” of the invention is aSNP-containing nucleic acid molecule whose amount has been increased atleast two fold by any nucleic acid amplification method performed invitro as compared to its starting amount in a test sample. In otherpreferred embodiments, an amplified polynucleotide is the result of atleast ten-fold, fifty-fold, one hundred-fold, one thousand-fold, or tenthousand-fold increase as compared to its starting amount in a testsample. In a typical PCR amplification, a polynucleotide of interest isoften amplified at least fifty thousand-fold in amount over theunamplified genomic DNA, but the precise amount of amplification neededfor an assay typically depends on the sensitivity of the subsequentdetection method used.

Generally, an amplified polynucleotide is at least about 16 nucleotidesin length. More typically, an amplified polynucleotide is at least about20 nucleotides in length. In a preferred embodiment of the invention, anamplified polynucleotide is at least about 30 nucleotides in length. Ina more preferred embodiment of the invention, an amplifiedpolynucleotide is at least about 32, 40, 45, 50, or 60 nucleotides inlength. In yet another preferred embodiment of the invention, anamplified polynucleotide is at least about 100, 200, 300, 400, or 500nucleotides in length. While the total length of an amplifiedpolynucleotide of the invention can be as long as an exon, an intron orthe entire gene where the SNP of interest resides, an amplified productis typically up to about 1,000 nucleotides in length (although certainamplification methods may generate amplified products greater than 1000nucleotides in length). More preferably, an amplified polynucleotide isnot greater than about 600-700 nucleotides in length. It is understoodthat irrespective of the length of an amplified polynucleotide, a SNP ofinterest may be located anywhere along its sequence.

In a specific embodiment of the invention, the amplified product is atleast about 201 nucleotides in length, comprises one of thetranscript-based context sequences or the genomic-based contextsequences shown in Tables 1-2. Such a product may have additionalsequences on its 5′ end or 3′ end or both. In another embodiment, theamplified product is about 101 nucleotides in length, and it contains aSNP disclosed herein. Preferably, the SNP is located at the middle ofthe amplified product (e.g., at position 101 in an amplified productthat is 201 nucleotides in length, or at position 51 in an amplifiedproduct that is 101 nucleotides in length), or within 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 12, 15, or 20 nucleotides from the middle of the amplifiedproduct (however, as indicated above, the SNP of interest may be locatedanywhere along the length of the amplified product).

The present invention provides isolated nucleic acid molecules thatcomprise, consist of, or consist essentially of one or morepolynucleotide sequences that contain one or more SNPs disclosed herein,complements thereof, and SNP-containing fragments thereof.

Accordingly, the present invention provides nucleic acid molecules thatconsist of any of the nucleotide sequences shown in Table 1 and/or Table2 (transcript sequences are provided in Table 1 as SEQ ID NOS:1-80,genomic sequences are provided in Table 2 as SEQ ID NOS:260-435,transcript-based SNP context sequences are provided in Table 1 as SEQ IDNO:161-259, and genomic-based SNP context sequences are provided inTable 2 as SEQ ID NO:436-1566), or any nucleic acid molecule thatencodes any of the variant proteins provided in Table 1 (SEQ IDNOS:81-160). A nucleic acid molecule consists of a nucleotide sequencewhen the nucleotide sequence is the complete nucleotide sequence of thenucleic acid molecule.

The present invention further provides nucleic acid molecules thatconsist essentially of any of the nucleotide sequences shown in Table 1and/or Table 2 (transcript sequences are provided in Table 1 as SEQ IDNOS:1-80, genomic sequences are provided in Table 2 as SEQ IDNOS:260-435, transcript-based SNP context sequences are provided inTable 1 as SEQ ID NO:161-259, and genomic-based SNP context sequencesare provided in Table 2 as SEQ ID NO:436-1566), or any nucleic acidmolecule that encodes any of the variant proteins provided in Table 1(SEQ ID NOS:81-160). A nucleic acid molecule consists essentially of anucleotide sequence when such a nucleotide sequence is present with onlya few additional nucleotide residues in the final nucleic acid molecule.

The present invention further provides nucleic acid molecules thatcomprise any of the nucleotide sequences shown in Table 1 and/or Table 2or a SNP-containing fragment thereof (transcript sequences are providedin Table 1 as SEQ ID NOS:1-80, genomic sequences are provided in Table 2as SEQ ID NOS:260-435, transcript-based SNP context sequences areprovided in Table 1 as SEQ ID NO:161-259, and genomic-based SNP contextsequences are provided in Table 2 as SEQ ID NO:436-1566), or any nucleicacid molecule that encodes any of the variant proteins provided in Table1 (SEQ ID NOS:81-160). A nucleic acid molecule comprises a nucleotidesequence when the nucleotide sequence is at least part of the finalnucleotide sequence of the nucleic acid molecule. In such a fashion, thenucleic acid molecule can be only the nucleotide sequence or haveadditional nucleotide residues, such as residues that are naturallyassociated with it or heterologous nucleotide sequences. Such a nucleicacid molecule can have one to a few additional nucleotides or cancomprise many more additional nucleotides. A brief description of howvarious types of these nucleic acid molecules can be readily made andisolated is provided below, and such techniques are well known to thoseof ordinary skill in the art (Sambrook and Russell, 2000, MolecularCloning: A Laboratory Manual, Cold Spring Harbor Press, NY).

The isolated nucleic acid molecules can encode mature proteins plusadditional amino or carboxyl-terminal amino acids or both, or aminoacids interior to the mature peptide (when the mature form has more thanone peptide chain, for instance). Such sequences may play a role inprocessing of a protein from precursor to a mature form, facilitateprotein trafficking, prolong or shorten protein half-life, or facilitatemanipulation of a protein for assay or production. As generally is thecase in situ, the additional amino acids may be processed away from themature protein by cellular enzymes.

Thus, the isolated nucleic acid molecules include, but are not limitedto, nucleic acid molecules having a sequence encoding a peptide alone, asequence encoding a mature peptide and additional coding sequences suchas a leader or secretory sequence (e.g., a pre-pro or pro-proteinsequence), a sequence encoding a mature peptide with or withoutadditional coding sequences, plus additional non-coding sequences, forexample introns and non-coding 5′ and 3′ sequences such as transcribedbut untranslated sequences that play a role in, for example,transcription, mRNA processing (including splicing and polyadenylationsignals), ribosome binding, and/or stability of mRNA. In addition, thenucleic acid molecules may be fused to heterologous marker sequencesencoding, for example, a peptide that facilitates purification.

Isolated nucleic acid molecules can be in the form of RNA, such as mRNA,or in the form DNA, including cDNA and genomic DNA, which may beobtained, for example, by molecular cloning or produced by chemicalsynthetic techniques or by a combination thereof (Sambrook and Russell,2000, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press,NY). Furthermore, isolated nucleic acid molecules, particularly SNPdetection reagents such as probes and primers, can also be partially orcompletely in the form of one or more types of nucleic acid analogs,such as peptide nucleic acid (PNA) (U.S. Pat. Nos. 5,539,082; 5,527,675;5,623,049; 5,714,331). The nucleic acid, especially DNA, can bedouble-stranded or single-stranded. Single-stranded nucleic acid can bethe coding strand (sense strand) or the complementary non-coding strand(anti-sense strand). DNA, RNA, or PNA segments can be assembled, forexample, from fragments of the human genome (in the case of DNA or RNA)or single nucleotides, short oligonucleotide linkers, or from a seriesof oligonucleotides, to provide a synthetic nucleic acid molecule.Nucleic acid molecules can be readily synthesized using the sequencesprovided herein as a reference; oligonucleotide and PNA oligomersynthesis techniques are well known in the art (see, e.g., Corey,“Peptide nucleic acids: expanding the scope of nucleic acidrecognition”, Trends Biotechnol. 1997 June; 15(6):224-9, and Hyrup etal., “Peptide nucleic acids (PNA): synthesis, properties and potentialapplications”, Bioorg Med Chem. 1996 January; 4(1):5-23). Furthermore,large-scale automated oligonucleotide/PNA synthesis (including synthesison an array or bead surface or other solid support) can readily beaccomplished using commercially available nucleic acid synthesizers,such as the Applied Biosystems (Foster City, Calif.) 3900High-Throughput DNA Synthesizer or Expedite 8909 Nucleic Acid SynthesisSystem, and the sequence information provided herein.

The present invention encompasses nucleic acid analogs that containmodified, synthetic, or non-naturally occurring nucleotides orstructural elements or other alternative/modified nucleic acidchemistries known in the art. Such nucleic acid analogs are useful, forexample, as detection reagents (e.g., primers/probes) for detecting oneor more SNPs identified in Table 1 and/or Table 2. Furthermore,kits/systems (such as beads, arrays, etc.) that include these analogsare also encompassed by the present invention. For example, PNAoligomers that are based on the polymorphic sequences of the presentinvention are specifically contemplated. PNA oligomers are analogs ofDNA in which the phosphate backbone is replaced with a peptide-likebackbone (Lagriffoul et al., Bioorganic & Medicinal Chemistry Letters,4: 1081-1082 (1994), Petersen et al., Bioorganic & Medicinal ChemistryLetters, 6: 793-796 (1996), Kumar et al., Organic Letters 3(9):1269-1272 (2001), WO96/04000). PNA hybridizes to complementary RNA orDNA with higher affinity and specificity than conventionaloligonucleotides and oligonucleotide analogs. The properties of PNAenable novel molecular biology and biochemistry applicationsunachievable with traditional oligonucleotides and peptides.

Additional examples of nucleic acid modifications that improve thebinding properties and/or stability of a nucleic acid include the use ofbase analogs such as inosine, intercalators (U.S. Pat. No. 4,835,263)and the minor groove binders (U.S. Pat. No. 5,801,115). Thus, referencesherein to nucleic acid molecules, SNP-containing nucleic acid molecules,SNP detection reagents (e.g., probes and primers),oligonucleotides/polynucleotides include PNA oligomers and other nucleicacid analogs. Other examples of nucleic acid analogs andalternative/modified nucleic acid chemistries known in the art aredescribed in Current Protocols in Nucleic Acid Chemistry, John Wiley &Sons, N.Y. (2002).

The present invention further provides nucleic acid molecules thatencode fragments of the variant polypeptides disclosed herein as well asnucleic acid molecules that encode obvious variants of such variantpolypeptides. Such nucleic acid molecules may be naturally occurring,such as paralogs (different locus) and orthologs (different organism),or may be constructed by recombinant DNA methods or by chemicalsynthesis. Non-naturally occurring variants may be made by mutagenesistechniques, including those applied to nucleic acid molecules, cells, ororganisms. Accordingly, the variants can contain nucleotidesubstitutions, deletions, inversions and insertions (in addition to theSNPs disclosed in Tables 1-2). Variation can occur in either or both thecoding and non-coding regions. The variations can produce conservativeand/or non-conservative amino acid substitutions.

Further variants of the nucleic acid molecules disclosed in Tables 1-2,such as naturally occurring allelic variants (as well as orthologs andparalogs) and synthetic variants produced by mutagenesis techniques, canbe identified and/or produced using methods well known in the art. Suchfurther variants can comprise a nucleotide sequence that shares at least70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity with a nucleic acid sequence disclosed in Table 1and/or Table 2 (or a fragment thereof) and that includes a novel SNPallele disclosed in Table 1 and/or Table 2. Further, variants cancomprise a nucleotide sequence that encodes a polypeptide that shares atleast 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or99% sequence identity with a polypeptide sequence disclosed in Table 1(or a fragment thereof) and that includes a novel SNP allele disclosedin Table 1 and/or Table 2. Thus, an aspect of the present invention thatis specifically contemplated are isolated nucleic acid molecules thathave a certain degree of sequence variation compared with the sequencesshown in Tables 1-2, but that contain a novel SNP allele disclosedherein. In other words, as long as an isolated nucleic acid moleculecontains a novel SNP allele disclosed herein, other portions of thenucleic acid molecule that flank the novel SNP allele can vary to somedegree from the specific transcript, genomic, and context sequencesshown in Tables 1-2, and can encode a polypeptide that varies to somedegree from the specific polypeptide sequences shown in Table 1.

To determine the percent identity of two amino acid sequences or twonucleotide sequences of two molecules that share sequence homology, thesequences are aligned for optimal comparison purposes (e.g., gaps can beintroduced in one or both of a first and a second amino acid or nucleicacid sequence for optimal alignment and non-homologous sequences can bedisregarded for comparison purposes). In a preferred embodiment, atleast 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more of the length of areference sequence is aligned for comparison purposes. The amino acidresidues or nucleotides at corresponding amino acid positions ornucleotide positions are then compared. When a position in the firstsequence is occupied by the same amino acid residue or nucleotide as thecorresponding position in the second sequence, then the molecules areidentical at that position (as used herein, amino acid or nucleic acid“identity” is equivalent to amino acid or nucleic acid “homology”). Thepercent identity between the two sequences is a function of the numberof identical positions shared by the sequences, taking into account thenumber of gaps, and the length of each gap, which need to be introducedfor optimal alignment of the two sequences.

The comparison of sequences and determination of percent identitybetween two sequences can be accomplished using a mathematicalalgorithm. (Computational Molecular Biology, Lesk, A. M., ed., OxfordUniversity Press, New York, 1988; Biocomputing: Informatics and GenomeProjects, Smith, D. W., ed., Academic Press, New York, 1993; ComputerAnalysis of Sequence Data, Part 1, Griffin, A. M., and Griffin, H. G.,eds., Humana Press, New Jersey, 1994; Sequence Analysis in MolecularBiology, von Heinje, G., Academic Press, 1987; and Sequence AnalysisPrimer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York,1991). In a preferred embodiment, the percent identity between two aminoacid sequences is determined using the Needleman and Wunsch algorithm(J. Mol. Biol. (48):444-453 (1970)) which has been incorporated into theGAP program in the GCG software package, using either a Blossom 62matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or4 and a length weight of 1, 2, 3, 4, 5, or 6.

In yet another preferred embodiment, the percent identity between twonucleotide sequences is determined using the GAP program in the GCGsoftware package (Devereux, J., et al., Nucleic Acids Res. 12(1):387(1984)), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60,70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. In anotherembodiment, the percent identity between two amino acid or nucleotidesequences is determined using the algorithm of E. Myers and W. Miller(CABIOS, 4:11-17 (1989)) which has been incorporated into the ALIGNprogram (version 2.0), using a PAM120 weight residue table, a gap lengthpenalty of 12, and a gap penalty of 4.

The nucleotide and amino acid sequences of the present invention canfurther be used as a “query sequence” to perform a search againstsequence databases to, for example, identify other family members orrelated sequences. Such searches can be performed using the NBLAST andXBLAST programs (version 2.0) of Altschul, et al. (J. Mol. Biol.215:403-10 (1990)). BLAST nucleotide searches can be performed with theNBLAST program, score=100, wordlength=12 to obtain nucleotide sequenceshomologous to the nucleic acid molecules of the invention. BLAST proteinsearches can be performed with the XBLAST program, score=50,wordlength=3 to obtain amino acid sequences homologous to the proteinsof the invention. To obtain gapped alignments for comparison purposes,Gapped BLAST can be utilized as described in Altschul et al. (NucleicAcids Res. 25(17):3389-3402 (1997)). When utilizing BLAST and gappedBLAST programs, the default parameters of the respective programs (e.g.,XBLAST and NBLAST) can be used. In addition to BLAST, examples of othersearch and sequence comparison programs used in the art include, but arenot limited to, FASTA (Pearson, Methods Mol. Biol. 25, 365-389 (1994))and KERR (Dufresne et al., Nat Biotechnol 2002 December;20(12):1269-71). For further information regarding bioinformaticstechniques, see Current Protocols in Bioinformatics, John Wiley & Sons,Inc., N.Y.

The present invention further provides non-coding fragments of thenucleic acid molecules disclosed in Table 1 and/or Table 2. Preferrednon-coding fragments include, but are not limited to, promotersequences, enhancer sequences, intronic sequences, 5′ untranslatedregions (UTRs), 3′ untranslated regions, gene modulating sequences andgene termination sequences. Such fragments are useful, for example, incontrolling heterologous gene expression and in developing screens toidentify gene-modulating agents.

SNP Detection Reagents

In a specific aspect of the present invention, the SNPs disclosed inTable 1 and/or Table 2, and their associated transcript sequences(provided in Table 1 as SEQ ID NOS:1-80), genomic sequences (provided inTable 2 as SEQ ID NOS:260-435), and context sequences (transcript-basedcontext sequences are provided in Table 1 as SEQ ID NOS:161-259;genomic-based context sequences are provided in Table 2 as SEQ IDNOS:436-1566), can be used for the design of SNP detection reagents. Asused herein, a “SNP detection reagent” is a reagent that specificallydetects a specific target SNP position disclosed herein, and that ispreferably specific for a particular nucleotide (allele) of the targetSNP position (i.e., the detection reagent preferably can differentiatebetween different alternative nucleotides at a target SNP position,thereby allowing the identity of the nucleotide present at the targetSNP position to be determined). Typically, such detection reagenthybridizes to a target SNP-containing nucleic acid molecule bycomplementary base-pairing in a sequence specific manner, anddiscriminates the target variant sequence from other nucleic acidsequences such as an art-known form in a test sample. An example of adetection reagent is a probe that hybridizes to a target nucleic acidcontaining one or more of the SNPs provided in Table 1 and/or Table 2.In a preferred embodiment, such a probe can differentiate betweennucleic acids having a particular nucleotide (allele) at a target SNPposition from other nucleic acids that have a different nucleotide atthe same target SNP position. In addition, a detection reagent mayhybridize to a specific region 5′ and/or 3′ to a SNP position,particularly a region corresponding to the context sequences provided inTable 1 and/or Table 2 (transcript-based context sequences are providedin Table 1 as SEQ ID NOS:161-259; genomic-based context sequences areprovided in Table 2 as SEQ ID NOS:436-1566). Another example of adetection reagent is a primer which acts as an initiation point ofnucleotide extension along a complementary strand of a targetpolynucleotide. The SNP sequence information provided herein is alsouseful for designing primers, e.g. allele-specific primers, to amplify(e.g., using PCR) any SNP of the present invention.

In one preferred embodiment of the invention, a SNP detection reagent isan isolated or synthetic DNA or RNA polynucleotide probe or primer orPNA oligomer, or a combination of DNA, RNA and/or PNA, that hybridizesto a segment of a target nucleic acid molecule containing a SNPidentified in Table 1 and/or Table 2. A detection reagent in the form ofa polynucleotide may optionally contain modified base analogs,intercalators or minor groove binders. Multiple detection reagents suchas probes may be, for example, affixed to a solid support (e.g., arraysor beads) or supplied in solution (e.g., probe/primer sets for enzymaticreactions such as PCR, RT-PCR, TaqMan assays, or primer-extensionreactions) to form a SNP detection kit.

A probe or primer typically is a substantially purified oligonucleotideor PNA oligomer. Such oligonucleotide typically comprises a region ofcomplementary nucleotide sequence that hybridizes under stringentconditions to at least about 8, 10, 12, 16, 18, 20, 22, 25, 30, 40, 50,55, 60, 65, 70, 80, 90, 100, 120 (or any other number in-between) ormore consecutive nucleotides in a target nucleic acid molecule.Depending on the particular assay, the consecutive nucleotides caneither include the target SNP position, or be a specific region in closeenough proximity 5′ and/or 3′ to the SNP position to carry out thedesired assay.

Other preferred primer and probe sequences can readily be determinedusing the transcript sequences (SEQ ID NOS:1-80), genomic sequences (SEQID NOS:260-435), and SNP context sequences (transcript-based contextsequences are provided in Table 1 as SEQ ID NOS:161-259; genomic-basedcontext sequences are provided in Table 2 as SEQ ID NOS:436-1566)disclosed in the Sequence Listing and in Tables 1-2. It will be apparentto one of skill in the art that such primers and probes are directlyuseful as reagents for genotyping the SNPs of the present invention, andcan be incorporated into any kit/system format.

In order to produce a probe or primer specific for a targetSNP-containing sequence, the gene/transcript and/or context sequencesurrounding the SNP of interest is typically examined using a computeralgorithm which starts at the 5′ or at the 3′ end of the nucleotidesequence. Typical algorithms will then identify oligomers of definedlength that are unique to the gene/SNP context sequence, have a GCcontent within a range suitable for hybridization, lack predictedsecondary structure that may interfere with hybridization, and/orpossess other desired characteristics or that lack other undesiredcharacteristics.

A primer or probe of the present invention is typically at least about 8nucleotides in length. In one embodiment of the invention, a primer or aprobe is at least about 10 nucleotides in length. In a preferredembodiment, a primer or a probe is at least about 12 nucleotides inlength. In a more preferred embodiment, a primer or probe is at leastabout 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 nucleotides in length.While the maximal length of a probe can be as long as the targetsequence to be detected, depending on the type of assay in which it isemployed, it is typically less than about 50, 60, 65, or 70 nucleotidesin length. In the case of a primer, it is typically less than about 30nucleotides in length. In a specific preferred embodiment of theinvention, a primer or a probe is within the length of about 18 andabout 28 nucleotides. However, in other embodiments, such as nucleicacid arrays and other embodiments in which probes are affixed to asubstrate, the probes can be longer, such as on the order of 30-70, 75,80, 90, 100, or more nucleotides in length (see the section belowentitled “SNP Detection Kits and Systems”).

For analyzing SNPs, it may be appropriate to use oligonucleotidesspecific for alternative SNP alleles. Such oligonucleotides which detectsingle nucleotide variations in target sequences may be referred to bysuch terms as “allele-specific oligonucleotides”, “allele-specificprobes”, or “allele-specific primers”. The design and use ofallele-specific probes for analyzing polymorphisms is described in,e.g., Mutation Detection A Practical Approach, ed. Cotton et al. OxfordUniversity Press, 1998; Saiki et al., Nature 324, 163-166 (1986);Dattagupta, EP235,726; and Saiki, WO 89/11548.

While the design of each allele-specific primer or probe depends onvariables such as the precise composition of the nucleotide sequencesflanking a SNP position in a target nucleic acid molecule, and thelength of the primer or probe, another factor in the use of primers andprobes is the stringency of the condition under which the hybridizationbetween the probe or primer and the target sequence is performed. Higherstringency conditions utilize buffers with lower ionic strength and/or ahigher reaction temperature, and tend to require a more perfect matchbetween probe/primer and a target sequence in order to form a stableduplex. If the stringency is too high, however, hybridization may notoccur at all. In contrast, lower stringency conditions utilize bufferswith higher ionic strength and/or a lower reaction temperature, andpermit the formation of stable duplexes with more mismatched basesbetween a probe/primer and a target sequence. By way of example and notlimitation, exemplary conditions for high stringency hybridizationconditions using an allele-specific probe are as follows:Prehybridization with a solution containing 5× standard saline phosphateEDTA (SSPE), 0.5% NaDodSO₄ (SDS) at 55° C., and incubating probe withtarget nucleic acid molecules in the same solution at the sametemperature, followed by washing with a solution containing 2×SSPE, and0.1% SDS at 55° C. or room temperature.

Moderate stringency hybridization conditions may be used forallele-specific primer extension reactions with a solution containing,e.g., about 50 mM KCl at about 46° C. Alternatively, the reaction may becarried out at an elevated temperature such as 60° C. In anotherembodiment, a moderately stringent hybridization condition suitable foroligonucleotide ligation assay (OLA) reactions wherein two probes areligated if they are completely complementary to the target sequence mayutilize a solution of about 100 mM KCl at a temperature of 46° C.

In a hybridization-based assay, allele-specific probes can be designedthat hybridize to a segment of target DNA from one individual but do nothybridize to the corresponding segment from another individual due tothe presence of different polymorphic forms (e.g., alternative SNPalleles/nucleotides) in the respective DNA segments from the twoindividuals. Hybridization conditions should be sufficiently stringentthat there is a significant detectable difference in hybridizationintensity between alleles, and preferably an essentially binaryresponse, whereby a probe hybridizes to only one of the alleles orsignificantly more strongly to one allele. While a probe may be designedto hybridize to a target sequence that contains a SNP site such that theSNP site aligns anywhere along the sequence of the probe, the probe ispreferably designed to hybridize to a segment of the target sequencesuch that the SNP site aligns with a central position of the probe(e.g., a position within the probe that is at least three nucleotidesfrom either end of the probe). This design of probe generally achievesgood discrimination in hybridization between different allelic forms.

In another embodiment, a probe or primer may be designed to hybridize toa segment of target DNA such that the SNP aligns with either the 5′ mostend or the 3′ most end of the probe or primer. In a specific preferredembodiment which is particularly suitable for use in a oligonucleotideligation assay (U.S. Pat. No. 4,988,617), the 3′ most nucleotide of theprobe aligns with the SNP position in the target sequence.

Oligonucleotide probes and primers may be prepared by methods well knownin the art. Chemical synthetic methods include, but are limited to, thephosphotriester method described by Narang et al., 1979, Methods inEnzymology 68:90; the phosphodiester method described by Brown et al.,1979, Methods in Enzymology 68:109, the diethylphosphoamidate methoddescribed by Beaucage et al., 1981, Tetrahedron Letters 22:1859; and thesolid support method described in U.S. Pat. No. 4,458,066.

Allele-specific probes are often used in pairs (or, less commonly, insets of 3 or 4, such as if a SNP position is known to have 3 or 4alleles, respectively, or to assay both strands of a nucleic acidmolecule for a target SNP allele), and such pairs may be identicalexcept for a one nucleotide mismatch that represents the allelicvariants at the SNP position. Commonly, one member of a pair perfectlymatches a reference form of a target sequence that has a more common SNPallele (i.e., the allele that is more frequent in the target population)and the other member of the pair perfectly matches a form of the targetsequence that has a less common SNP allele (i.e., the allele that israrer in the target population). In the case of an array, multiple pairsof probes can be immobilized on the same support for simultaneousanalysis of multiple different polymorphisms.

In one type of PCR-based assay, an allele-specific primer hybridizes toa region on a target nucleic acid molecule that overlaps a SNP positionand only primes amplification of an allelic form to which the primerexhibits perfect complementarity (Gibbs, 1989, Nucleic Acid Res. 172427-2448). Typically, the primer's 3′-most nucleotide is aligned withand complementary to the SNP position of the target nucleic acidmolecule. This primer is used in conjunction with a second primer thathybridizes at a distal site. Amplification proceeds from the twoprimers, producing a detectable product that indicates which allelicform is present in the test sample. A control is usually performed witha second pair of primers, one of which shows a single base mismatch atthe polymorphic site and the other of which exhibits perfectcomplementarity to a distal site. The single-base mismatch preventsamplification or substantially reduces amplification efficiency, so thateither no detectable product is formed or it is formed in lower amountsor at a slower pace. The method generally works most effectively whenthe mismatch is at the 3′-most position of the oligonucleotide (i.e.,the 3′-most position of the oligonucleotide aligns with the target SNPposition) because this position is most destabilizing to elongation fromthe primer (see, e.g., WO 93/22456). This PCR-based assay can beutilized as part of the TaqMan assay, described below.

In a specific embodiment of the invention, a primer of the inventioncontains a sequence substantially complementary to a segment of a targetSNP-containing nucleic acid molecule except that the primer has amismatched nucleotide in one of the three nucleotide positions at the3′-most end of the primer, such that the mismatched nucleotide does notbase pair with a particular allele at the SNP site. In a preferredembodiment, the mismatched nucleotide in the primer is the second fromthe last nucleotide at the 3′-most position of the primer. In a morepreferred embodiment, the mismatched nucleotide in the primer is thelast nucleotide at the 3′-most position of the primer.

In another embodiment of the invention, a SNP detection reagent of theinvention is labeled with a fluorogenic reporter dye that emits adetectable signal. While the preferred reporter dye is a fluorescentdye, any reporter dye that can be attached to a detection reagent suchas an oligonucleotide probe or primer is suitable for use in theinvention. Such dyes include, but are not limited to, Acridine, AMCA,BODIPY, Cascade Blue, Cy2, Cy3, Cy5, Cy7, Dabcyl, Edans, Eosin,Erythrosin, Fluorescein, 6-Fam, Tet, Joe, Hex, Oregon Green, Rhodamine,Rhodol Green, Tamra, Rox, and Texas Red.

In yet another embodiment of the invention, the detection reagent may befurther labeled with a quencher dye such as Tamra, especially when thereagent is used as a self-quenching probe such as a TaqMan (U.S. Pat.Nos. 5,210,015 and 5,538,848) or Molecular Beacon probe (U.S. Pat. Nos.5,118,801 and 5,312,728), or other stemless or linear beacon probe(Livak et al., 1995, PCR Method Appl. 4:357-362; Tyagi et al., 1996,Nature Biotechnology 14: 303-308; Nazarenko et al., 1997, Nucl. AcidsRes. 25:2516-2521; U.S. Pat. Nos. 5,866,336 and 6,117,635).

The detection reagents of the invention may also contain other labels,including but not limited to, biotin for streptavidin binding, haptenfor antibody binding, and oligonucleotide for binding to anothercomplementary oligonucleotide such as pairs of zipcodes.

The present invention also contemplates reagents that do not contain (orthat are complementary to) a SNP nucleotide identified herein but thatare used to assay one or more SNPs disclosed herein. For example,primers that flank, but do not hybridize directly to a target SNPposition provided herein are useful in primer extension reactions inwhich the primers hybridize to a region adjacent to the target SNPposition (i.e., within one or more nucleotides from the target SNPsite). During the primer extension reaction, a primer is typically notable to extend past a target SNP site if a particular nucleotide(allele) is present at that target SNP site, and the primer extensionproduct can be detected in order to determine which SNP allele ispresent at the target SNP site. For example, particular ddNTPs aretypically used in the primer extension reaction to terminate primerextension once a ddNTP is incorporated into the extension product (aprimer extension product which includes a ddNTP at the 3′-most end ofthe primer extension product, and in which the ddNTP is a nucleotide ofa SNP disclosed herein, is a composition that is specificallycontemplated by the present invention). Thus, reagents that bind to anucleic acid molecule in a region adjacent to a SNP site and that areused for assaying the SNP site, even though the bound sequences do notnecessarily include the SNP site itself, are also contemplated by thepresent invention.

SNP Detection Kits and Systems

A person skilled in the art will recognize that, based on the SNP andassociated sequence information disclosed herein, detection reagents canbe developed and used to assay any SNP of the present inventionindividually or in combination, and such detection reagents can bereadily incorporated into one of the established kit or system formatswhich are well known in the art. The terms “kits” and “systems”, as usedherein in the context of SNP detection reagents, are intended to referto such things as combinations of multiple SNP detection reagents, orone or more SNP detection reagents in combination with one or more othertypes of elements or components (e.g., other types of biochemicalreagents, containers, packages such as packaging intended for commercialsale, substrates to which SNP detection reagents are attached,electronic hardware components, etc.). Accordingly, the presentinvention further provides SNP detection kits and systems, including butnot limited to, packaged probe and primer sets (e.g., TaqManprobe/primer sets), arrays/microarrays of nucleic acid molecules, andbeads that contain one or more probes, primers, or other detectionreagents for detecting one or more SNPs of the present invention. Thekits/systems can optionally include various electronic hardwarecomponents; for example, arrays (“DNA chips”) and microfluidic systems(“lab-on-a-chip” systems) provided by various manufacturers typicallycomprise hardware components. Other kits/systems (e.g., probe/primersets) may not include electronic hardware components, but may becomprised of, for example, one or more SNP detection reagents (alongwith, optionally, other biochemical reagents) packaged in one or morecontainers.

In some embodiments, a SNP detection kit typically contains one or moredetection reagents and other components (e.g., a buffer, enzymes such asDNA polymerases or ligases, chain extension nucleotides such asdeoxynucleotide triphosphates, and in the case of Sanger-type DNAsequencing reactions, chain terminating nucleotides, positive controlsequences, negative control sequences, and the like) necessary to carryout an assay or reaction, such as amplification and/or detection of aSNP-containing nucleic acid molecule. A kit may further contain meansfor determining the amount of a target nucleic acid, and means forcomparing the amount with a standard, and can comprise instructions forusing the kit to detect the SNP-containing nucleic acid molecule ofinterest. In one embodiment of the present invention, kits are providedwhich contain the necessary reagents to carry out one or more assays todetect one or more SNPs disclosed herein. In a preferred embodiment ofthe present invention, SNP detection kits/systems are in the form ofnucleic acid arrays, or compartmentalized kits, includingmicrofluidic/lab-on-a-chip systems.

SNP detection kits/systems may contain, for example, one or more probes,or pairs of probes, that hybridize to a nucleic acid molecule at or neareach target SNP position. Multiple pairs of allele-specific probes maybe included in the kit/system to simultaneously assay large numbers ofSNPs, at least one of which is a SNP of the present invention. In somekits/systems, the allele-specific probes are immobilized to a substratesuch as an array or bead. For example, the same substrate can compriseallele-specific probes for detecting at least 1; 10; 100; 1000; 10,000;100,000 (or any other number in-between) or substantially all of theSNPs shown in Table 1 and/or Table 2.

The terms “arrays”, “microarrays”, and “DNA chips” are used hereininterchangeably to refer to an array of distinct polynucleotides affixedto a substrate, such as glass, plastic, paper, nylon or other type ofmembrane, filter, chip, or any other suitable solid support. Thepolynucleotides can be synthesized directly on the substrate, orsynthesized separate from the substrate and then affixed to thesubstrate. In one embodiment, the microarray is prepared and usedaccording to the methods described in U.S. Pat. No. 5,837,832, Chee etal., PCT application WO95/11995 (Chee et al.), Lockhart, D. J. et al.(1996; Nat. Biotech. 14: 1675-1680) and Schena, M. et al. (1996; Proc.Natl. Acad. Sci. 93: 10614-10619), all of which are incorporated hereinin their entirety by reference. In other embodiments, such arrays areproduced by the methods described by Brown et al., U.S. Pat. No.5,807,522.

Nucleic acid arrays are reviewed in the following references: Zammatteoet al., “New chips for molecular biology and diagnostics”, BiotechnolAnnu Rev. 2002; 8:85-101; Sosnowski et al., “Active microelectronicarray system for DNA hybridization, genotyping and pharmacogenomicapplications”, Psychiatr Genet. 2002 December; 12(4):181-92; Heller,“DNA microarray technology: devices, systems, and applications”, AnnuRev Biomed Eng. 2002; 4:129-53. Epub 2002 Mar. 22; Kolchinsky et al.,“Analysis of SNPs and other genomic variations using gel-based chips”,Hum Mutat. 2002 April; 19(4):343-60; and McGall et al., “High-densitygenechip oligonucleotide probe arrays”, Adv Biochem Eng Biotechnol.2002; 77:21-42.

Any number of probes, such as allele-specific probes, may be implementedin an array, and each probe or pair of probes can hybridize to adifferent SNP position. In the case of polynucleotide probes, they canbe synthesized at designated areas (or synthesized separately and thenaffixed to designated areas) on a substrate using a light-directedchemical process. Each DNA chip can contain, for example, thousands tomillions of individual synthetic polynucleotide probes arranged in agrid-like pattern and miniaturized (e.g., to the size of a dime).Preferably, probes are attached to a solid support in an ordered,addressable array.

A microarray can be composed of a large number of unique,single-stranded polynucleotides, usually either synthetic antisensepolynucleotides or fragments of cDNAs, fixed to a solid support. Typicalpolynucleotides are preferably about 6-60 nucleotides in length, morepreferably about 15-30 nucleotides in length, and most preferably about18-25 nucleotides in length. For certain types of microarrays or otherdetection kits/systems, it may be preferable to use oligonucleotidesthat are only about 7-20 nucleotides in length. In other types ofarrays, such as arrays used in conjunction with chemiluminescentdetection technology, preferred probe lengths can be, for example, about15-80 nucleotides in length, preferably about 50-70 nucleotides inlength, more preferably about 55-65 nucleotides in length, and mostpreferably about 60 nucleotides in length. The microarray or detectionkit can contain polynucleotides that cover the known 5′ or 3′ sequenceof a gene/transcript or target SNP site, sequential polynucleotides thatcover the full-length sequence of a gene/transcript; or uniquepolynucleotides selected from particular areas along the length of atarget gene/transcript sequence, particularly areas corresponding to oneor more SNPs disclosed in Table 1 and/or Table 2. Polynucleotides usedin the microarray or detection kit can be specific to a SNP or SNPs ofinterest (e.g., specific to a particular SNP allele at a target SNPsite, or specific to particular SNP alleles at multiple different SNPsites), or specific to a polymorphic gene/transcript orgenes/transcripts of interest.

Hybridization assays based on polynucleotide arrays rely on thedifferences in hybridization stability of the probes to perfectlymatched and mismatched target sequence variants. For SNP genotyping, itis generally preferable that stringency conditions used in hybridizationassays are high enough such that nucleic acid molecules that differ fromone another at as little as a single SNP position can be differentiated(e.g., typical SNP hybridization assays are designed so thathybridization will occur only if one particular nucleotide is present ata SNP position, but will not occur if an alternative nucleotide ispresent at that SNP position). Such high stringency conditions may bepreferable when using, for example, nucleic acid arrays ofallele-specific probes for SNP detection. Such high stringencyconditions are described in the preceding section, and are well known tothose skilled in the art and can be found in, for example, CurrentProtocols in Molecular Biology, John Wiley & Sons, N.Y. (1989),6.3.1-6.3.6.

In other embodiments, the arrays are used in conjunction withchemiluminescent detection technology. The following patents and patentapplications, which are all hereby incorporated by reference, provideadditional information pertaining to chemiluminescent detection: U.S.patent application Ser. Nos. 10/620,332 and 10/620,333 describechemiluminescent approaches for microarray detection; U.S. Pat. Nos.6,124,478, 6,107,024, 5,994,073, 5,981,768, 5,871,938, 5,843,681,5,800,999, and 5,773,628 describe methods and compositions of dioxetanefor performing chemiluminescent detection; and U.S. publishedapplication US2002/0110828 discloses methods and compositions formicroarray controls.

In one embodiment of the invention, a nucleic acid array can comprise anarray of probes of about 15-25 nucleotides in length. In furtherembodiments, a nucleic acid array can comprise any number of probes, inwhich at least one probe is capable of detecting one or more SNPsdisclosed in Table 1 and/or Table 2, and/or at least one probe comprisesa fragment of one of the sequences selected from the group consisting ofthose disclosed in Table 1, Table 2, the Sequence Listing, and sequencescomplementary thereto, said fragment comprising at least about 8consecutive nucleotides, preferably 10, 12, 15, 16, 18, 20, morepreferably 22, 25, 30, 40, 47, 50, 55, 60, 65, 70, 80, 90, 100, or moreconsecutive nucleotides (or any other number in-between) and containing(or being complementary to) a novel SNP allele disclosed in Table 1and/or Table 2. In some embodiments, the nucleotide complementary to theSNP site is within 5, 4, 3, 2, or 1 nucleotide from the center of theprobe, more preferably at the center of said probe.

A polynucleotide probe can be synthesized on the surface of thesubstrate by using a chemical coupling procedure and an ink jetapplication apparatus, as described in PCT application WO95/251116(Baldeschweiler et al.) which is incorporated herein in its entirety byreference. In another aspect, a “gridded” array analogous to a dot (orslot) blot may be used to arrange and link cDNA fragments oroligonucleotides to the surface of a substrate using a vacuum system,thermal, UV, mechanical or chemical bonding procedures. An array, suchas those described above, may be produced by hand or by using availabledevices (slot blot or dot blot apparatus), materials (any suitable solidsupport), and machines (including robotic instruments), and may contain8, 24, 96, 384, 1536, 6144 or more polynucleotides, or any other numberwhich lends itself to the efficient use of commercially availableinstrumentation.

Using such arrays or other kits/systems, the present invention providesmethods of identifying the SNPs disclosed herein in a test sample. Suchmethods typically involve incubating a test sample of nucleic acids withan array comprising one or more probes corresponding to at least one SNPposition of the present invention, and assaying for binding of a nucleicacid from the test sample with one or more of the probes. Conditions forincubating a SNP detection reagent (or a kit/system that employs one ormore such SNP detection reagents) with a test sample vary. Incubationconditions depend on such factors as the format employed in the assay,the detection methods employed, and the type and nature of the detectionreagents used in the assay. One skilled in the art will recognize thatany one of the commonly available hybridization, amplification and arrayassay formats can readily be adapted to detect the SNPs disclosedherein.

A SNP detection kit/system of the present invention may includecomponents that are used to prepare nucleic acids from a test sample forthe subsequent amplification and/or detection of a SNP-containingnucleic acid molecule. Such sample preparation components can be used toproduce nucleic acid extracts (including DNA and/or RNA), proteins ormembrane extracts from any bodily fluids (such as blood, serum, plasma,urine, saliva, phlegm, gastric juices, semen, tears, sweat, etc.), skin,hair, cells (especially nucleated cells), biopsies, buccal cells (e.g.,as obtained by buccal swabs), or tissue specimens. The test samples usedin the above-described methods will vary based on such factors as theassay format, nature of the detection method, and the specific tissues,cells or extracts used as the test sample to be assayed. Methods ofpreparing nucleic acids, proteins, and cell extracts are well known inthe art and can be readily adapted to obtain a sample that is compatiblewith the system utilized. Automated sample preparation systems forextracting nucleic acids from a test sample are commercially available,and examples are Qiagen's BioRobot 9600, Applied Biosystems' PRISM™ 6700sample preparation system, and Roche Molecular Systems' COBAS AmpliPrepSystem.

Another form of kit contemplated by the present invention is acompartmentalized kit. A compartmentalized kit includes any kit in whichreagents are contained in separate containers. Such containers include,for example, small glass containers, plastic containers, strips ofplastic, glass or paper, or arraying material such as silica. Suchcontainers allow one to efficiently transfer reagents from onecompartment to another compartment such that the test samples andreagents are not cross-contaminated, or from one container to anothervessel not included in the kit, and the agents or solutions of eachcontainer can be added in a quantitative fashion from one compartment toanother or to another vessel. Such containers may include, for example,one or more containers which will accept the test sample, one or morecontainers which contain at least one probe or other SNP detectionreagent for detecting one or more SNPs of the present invention, one ormore containers which contain wash reagents (such as phosphate bufferedsaline, Tris-buffers, etc.), and one or more containers which containthe reagents used to reveal the presence of the bound probe or other SNPdetection reagents. The kit can optionally further comprise compartmentsand/or reagents for, for example, nucleic acid amplification or otherenzymatic reactions such as primer extension reactions, hybridization,ligation, electrophoresis (preferably capillary electrophoresis), massspectrometry, and/or laser-induced fluorescent detection. The kit mayalso include instructions for using the kit. Exemplary compartmentalizedkits include microfluidic devices known in the art (see, e.g., Weigl etal., “Lab-on-a-chip for drug development”, Adv Drug Deliv Rev. 2003 Feb.24; 55(3):349-77). In such microfluidic devices, the containers may bereferred to as, for example, microfluidic “compartments”, “chambers”, or“channels”.

Microfluidic devices, which may also be referred to as “lab-on-a-chip”systems, biomedical micro-electro-mechanical systems (bioMEMs), ormulticomponent integrated systems, are exemplary kits/systems of thepresent invention for analyzing SNPs. Such systems miniaturize andcompartmentalize processes such as probe/target hybridization, nucleicacid amplification, and capillary electrophoresis reactions in a singlefunctional device. Such microfluidic devices typically utilize detectionreagents in at least one aspect of the system, and such detectionreagents may be used to detect one or more SNPs of the presentinvention. One example of a microfluidic system is disclosed in U.S.Pat. No. 5,589,136, which describes the integration of PCR amplificationand capillary electrophoresis in chips. Exemplary microfluidic systemscomprise a pattern of microchannels designed onto a glass, silicon,quartz, or plastic wafer included on a microchip. The movements of thesamples may be controlled by electric, electroosmotic or hydrostaticforces applied across different areas of the microchip to createfunctional microscopic valves and pumps with no moving parts. Varyingthe voltage can be used as a means to control the liquid flow atintersections between the micro-machined channels and to change theliquid flow rate for pumping across different sections of the microchip.See, for example, U.S. Pat. No. 6,153,073, Dubrow et al., and U.S. Pat.No. 6,156,181, Parce et al.

For genotyping SNPs, an exemplary microfluidic system may integrate, forexample, nucleic acid amplification, primer extension, capillaryelectrophoresis, and a detection method such as laser inducedfluorescence detection. In a first step of an exemplary process forusing such an exemplary system, nucleic acid samples are amplified,preferably by PCR. Then, the amplification products are subjected toautomated primer extension reactions using ddNTPs (specific fluorescencefor each ddNTP) and the appropriate oligonucleotide primers to carry outprimer extension reactions which hybridize just upstream of the targetedSNP. Once the extension at the 3′ end is completed, the primers areseparated from the unincorporated fluorescent ddNTPs by capillaryelectrophoresis. The separation medium used in capillary electrophoresiscan be, for example, polyacrylamide, polyethyleneglycol or dextran. Theincorporated ddNTPs in the single nucleotide primer extension productsare identified by laser-induced fluorescence detection. Such anexemplary microchip can be used to process, for example, at least 96 to384 samples, or more, in parallel.

Uses of Nucleic Acid Molecules

The nucleic acid molecules of the present invention have a variety ofuses, especially in the diagnosis and treatment of stroke and relatedpathologies. For example, the nucleic acid molecules are useful ashybridization probes, such as for genotyping SNPs in messenger RNA,transcript, cDNA, genomic DNA, amplified DNA or other nucleic acidmolecules, and for isolating full-length cDNA and genomic clonesencoding the variant peptides disclosed in Table 1 as well as theirorthologs.

A probe can hybridize to any nucleotide sequence along the entire lengthof a nucleic acid molecule provided in Table 1 and/or Table 2.Preferably, a probe of the present invention hybridizes to a region of atarget sequence that encompasses a SNP position indicated in Table 1and/or Table 2. More preferably, a probe hybridizes to a SNP-containingtarget sequence in a sequence-specific manner such that it distinguishesthe target sequence from other nucleotide sequences which vary from thetarget sequence only by which nucleotide is present at the SNP site.Such a probe is particularly useful for detecting the presence of aSNP-containing nucleic acid in a test sample, or for determining whichnucleotide (allele) is present at a particular SNP site (i.e.,genotyping the SNP site).

A nucleic acid hybridization probe may be used for determining thepresence, level, form, and/or distribution of nucleic acid expression.The nucleic acid whose level is determined can be DNA or RNA.Accordingly, probes specific for the SNPs described herein can be usedto assess the presence, expression and/or gene copy number in a givencell, tissue, or organism. These uses are relevant for diagnosis ofdisorders involving an increase or decrease in gene expression relativeto normal levels. In vitro techniques for detection of mRNA include, forexample, Northern blot hybridizations and in situ hybridizations. Invitro techniques for detecting DNA include Southern blot hybridizationsand in situ hybridizations (Sambrook and Russell, 2000, MolecularCloning: A Laboratory Manual, Cold Spring Harbor Press, Cold SpringHarbor, N.Y.).

Probes can be used as part of a diagnostic test kit for identifyingcells or tissues in which a variant protein is expressed, such as bymeasuring the level of a variant protein-encoding nucleic acid (e.g.,mRNA) in a sample of cells from a subject or determining if apolynucleotide contains a SNP of interest.

Thus, the nucleic acid molecules of the invention can be used ashybridization probes to detect the SNPs disclosed herein, therebydetermining whether an individual with the polymorphisms is at risk forstroke and related pathologies. Detection of a SNP associated with adisease phenotype provides a diagnostic tool for an active diseaseand/or genetic predisposition to the disease.

Furthermore, the nucleic acid molecules of the invention are thereforeuseful for detecting a gene (gene information is disclosed in Table 2,for example) which contains a SNP disclosed herein and/or products ofsuch genes, such as expressed mRNA transcript molecules (transcriptinformation is disclosed in Table 1, for example), and are thus usefulfor detecting gene expression. The nucleic acid molecules can optionallybe implemented in, for example, an array or kit format for use indetecting gene expression.

The nucleic acid molecules of the invention are also useful as primersto amplify any given region of a nucleic acid molecule, particularly aregion containing a SNP identified in Table 1 and/or Table 2.

The nucleic acid molecules of the invention are also useful forconstructing recombinant vectors (described in greater detail below).Such vectors include expression vectors that express a portion of, orall of, any of the variant peptide sequences provided in Table 1.Vectors also include insertion vectors, used to integrate into anothernucleic acid molecule sequence, such as into the cellular genome, toalter in situ expression of a gene and/or gene product. For example, anendogenous coding sequence can be replaced via homologous recombinationwith all or part of the coding region containing one or morespecifically introduced SNPs.

The nucleic acid molecules of the invention are also useful forexpressing antigenic portions of the variant proteins, particularlyantigenic portions that contain a variant amino acid sequence (e.g., anamino acid substitution) caused by a SNP disclosed in Table 1 and/orTable 2.

The nucleic acid molecules of the invention are also useful forconstructing vectors containing a gene regulatory region of the nucleicacid molecules of the present invention.

The nucleic acid molecules of the invention are also useful fordesigning ribozymes corresponding to all, or a part, of an mRNA moleculeexpressed from a SNP-containing nucleic acid molecule described herein.

The nucleic acid molecules of the invention are also useful forconstructing host cells expressing a part, or all, of the nucleic acidmolecules and variant peptides.

The nucleic acid molecules of the invention are also useful forconstructing transgenic animals expressing all, or a part, of thenucleic acid molecules and variant peptides. The production ofrecombinant cells and transgenic animals having nucleic acid moleculeswhich contain the SNPs disclosed in Table 1 and/or Table 2 allow, forexample, effective clinical design of treatment compounds and dosageregimens.

The nucleic acid molecules of the invention are also useful in assaysfor drug screening to identify compounds that, for example, modulatenucleic acid expression.

The nucleic acid molecules of the invention are also useful in genetherapy in patients whose cells have aberrant gene expression. Thus,recombinant cells, which include a patient's cells that have beenengineered ex vivo and returned to the patient, can be introduced intoan individual where the recombinant cells produce the desired protein totreat the individual.

SNP Genotyping Methods

The process of determining which specific nucleotide (i.e., allele) ispresent at each of one or more SNP positions, such as a SNP position ina nucleic acid molecule disclosed in Table 1 and/or Table 2, is referredto as SNP genotyping. The present invention provides methods of SNPgenotyping, such as for use in determining predisposition to stroke orrelated pathologies, or determining responsiveness to a form oftreatment, or in genome mapping or SNP association analysis, etc.

Nucleic acid samples can be genotyped to determine which allele(s)is/are present at any given genetic region (e.g., SNP position) ofinterest by methods well known in the art. The neighboring sequence canbe used to design SNP detection reagents such as oligonucleotide probes,which may optionally be implemented in a kit format. Exemplary SNPgenotyping methods are described in Chen et al., “Single nucleotidepolymorphism genotyping: biochemistry, protocol, cost and throughput”,Pharmacogenomics J. 2003; 3(2):77-96; Kwok et al., “Detection of singlenucleotide polymorphisms”, Curr Issues Mol Biol. 2003 April; 5(2):43-60;Shi, “Technologies for individual genotyping: detection of geneticpolymorphisms in drug targets and disease genes”, Am J Pharmacogenomics.2002; 2(3):197-205; and Kwok, “Methods for genotyping single nucleotidepolymorphisms”, Annu Rev Genomics Hum Genet 2001; 2:235-58. Exemplarytechniques for high-throughput SNP genotyping are described inMarnellos, “High-throughput SNP analysis for genetic associationstudies”, Curr Opin Drug Discov Devel. 2003 May; 6(3):317-21. Common SNPgenotyping methods include, but are not limited to, TaqMan assays,molecular beacon assays, nucleic acid arrays, allele-specific primerextension, allele-specific PCR, arrayed primer extension, homogeneousprimer extension assays, primer extension with detection by massspectrometry, pyrosequencing, multiplex primer extension sorted ongenetic arrays, ligation with rolling circle amplification, homogeneousligation, OLA (U.S. Pat. No. 4,988,167), multiplex ligation reactionsorted on genetic arrays, restriction-fragment length polymorphism,single base extension-tag assays, and the Invader assay. Such methodsmay be used in combination with detection mechanisms such as, forexample, luminescence or chemiluminescence detection, fluorescencedetection, time-resolved fluorescence detection, fluorescence resonanceenergy transfer, fluorescence polarization, mass spectrometry, andelectrical detection.

Various methods for detecting polymorphisms include, but are not limitedto, methods in which protection from cleavage agents is used to detectmismatched bases in RNA/RNA or RNA/DNA duplexes (Myers et A, Science230:1242 (1985); Cotton et al., PNAS 85:4397 (1988); and Saleeba et A,Meth. Enzymol. 217:286-295 (1992)), comparison of the electrophoreticmobility of variant and wild type nucleic acid molecules (Orita et al.,PNAS 86:2766 (1989); Cotton et A, Mutat. Res. 285:125-144 (1993); andHayashi et al., Genet. Anal. Tech. Appl. 9:73-79 (1992)), and assayingthe movement of polymorphic or wild-type fragments in polyacrylamidegels containing a gradient of denaturant using denaturing gradient gelelectrophoresis (DGGE) (Myers et al., Nature 313:495 (1985)). Sequencevariations at specific locations can also be assessed by nucleaseprotection assays such as RNase and 51 protection or chemical cleavagemethods.

In a preferred embodiment, SNP genotyping is performed using the TaqManassay, which is also known as the 5′ nuclease assay (U.S. Pat. Nos.5,210,015 and 5,538,848). The TaqMan assay detects the accumulation of aspecific amplified product during PCR. The TaqMan assay utilizes anoligonucleotide probe labeled with a fluorescent reporter dye and aquencher dye. The reporter dye is excited by irradiation at anappropriate wavelength, it transfers energy to the quencher dye in thesame probe via a process called fluorescence resonance energy transfer(FRET). When attached to the probe, the excited reporter dye does notemit a signal. The proximity of the quencher dye to the reporter dye inthe intact probe maintains a reduced fluorescence for the reporter. Thereporter dye and quencher dye may be at the 5′ most and the 3′ mostends, respectively, or vice versa. Alternatively, the reporter dye maybe at the 5′ or 3′ most end while the quencher dye is attached to aninternal nucleotide, or vice versa. In yet another embodiment, both thereporter and the quencher may be attached to internal nucleotides at adistance from each other such that fluorescence of the reporter isreduced.

During PCR, the 5′ nuclease activity of DNA polymerase cleaves theprobe, thereby separating the reporter dye and the quencher dye andresulting in increased fluorescence of the reporter. Accumulation of PCRproduct is detected directly by monitoring the increase in fluorescenceof the reporter dye. The DNA polymerase cleaves the probe between thereporter dye and the quencher dye only if the probe hybridizes to thetarget SNP-containing template which is amplified during PCR, and theprobe is designed to hybridize to the target SNP site only if aparticular SNP allele is present.

Preferred TaqMan primer and probe sequences can readily be determinedusing the SNP and associated nucleic acid sequence information providedherein. A number of computer programs, such as Primer Express (AppliedBiosystems, Foster City, Calif.), can be used to rapidly obtain optimalprimer/probe sets. It will be apparent to one of skill in the art thatsuch primers and probes for detecting the SNPs of the present inventionare useful in assays for determining predisposition to stroke andrelated pathologies, and can be readily incorporated into a kit format.The present invention also includes modifications of the Taqman assaywell known in the art such as the use of Molecular Beacon probes (U.S.Pat. Nos. 5,118,801 and 5,312,728) and other variant formats (U.S. Pat.Nos. 5,866,336 and 6,117,635).

Another preferred method for genotyping the SNPs of the presentinvention is the use of two oligonucleotide probes in an OLA (see, e.g.,U.S. Pat. No. 4,988,617). In this method, one probe hybridizes to asegment of a target nucleic acid with its 3′ most end aligned with theSNP site. A second probe hybridizes to an adjacent segment of the targetnucleic acid molecule directly 3′ to the first probe. The two juxtaposedprobes hybridize to the target nucleic acid molecule, and are ligated inthe presence of a linking agent such as a ligase if there is perfectcomplementarity between the 3′ most nucleotide of the first probe withthe SNP site. If there is a mismatch, ligation would not occur. Afterthe reaction, the ligated probes are separated from the target nucleicacid molecule, and detected as indicators of the presence of a SNP.

The following patents, patent applications, and published internationalpatent applications, which are all hereby incorporated by reference,provide additional information pertaining to techniques for carrying outvarious types of OLA: U.S. Pat. Nos. 6,027,889, 6,268,148, 5,494,810,5,830,711, and 6,054,564 describe OLA strategies for performing SNPdetection; WO 97/31256 and WO 00/56927 describe OLA strategies forperforming SNP detection using universal arrays, wherein a zipcodesequence can be introduced into one of the hybridization probes, and theresulting product, or amplified product, hybridized to a universal zipcode array; U.S. application US01/17329 (and Ser. No. 09/584,905)describes OLA (or LDR) followed by PCR, wherein zipcodes areincorporated into OLA probes, and amplified PCR products are determinedby electrophoretic or universal zipcode array readout; U.S. applications60/427,818, 60/445,636, and 60/445,494 describe SNPlex methods andsoftware for multiplexed SNP detection using OLA followed by PCR,wherein zipcodes are incorporated into OLA probes, and amplified PCRproducts are hybridized with a zipchute reagent, and the identity of theSNP determined from electrophoretic readout of the zipchute. In someembodiments, OLA is carried out prior to PCR (or another method ofnucleic acid amplification). In other embodiments, PCR (or anothermethod of nucleic acid amplification) is carried out prior to OLA.

Another method for SNP genotyping is based on mass spectrometry. Massspectrometry takes advantage of the unique mass of each of the fournucleotides of DNA. SNPs can be unambiguously genotyped by massspectrometry by measuring the differences in the mass of nucleic acidshaving alternative SNP alleles. MALDI-TOF (Matrix Assisted LaserDesorption Ionization—Time of Flight) mass spectrometry technology ispreferred for extremely precise determinations of molecular mass, suchas SNPs. Numerous approaches to SNP analysis have been developed basedon mass spectrometry. Preferred mass spectrometry-based methods of SNPgenotyping include primer extension assays, which can also be utilizedin combination with other approaches, such as traditional gel-basedformats and microarrays.

Typically, the primer extension assay involves designing and annealing aprimer to a template PCR amplicon upstream (5′) from a target SNPposition. A mix of dideoxynucleotide triphosphates (ddNTPs) and/ordeoxynucleotide triphosphates (dNTPs) are added to a reaction mixturecontaining template (e.g., a SNP-containing nucleic acid molecule whichhas typically been amplified, such as by PCR), primer, and DNApolymerase. Extension of the primer terminates at the first position inthe template where a nucleotide complementary to one of the ddNTPs inthe mix occurs. The primer can be either immediately adjacent (i.e., thenucleotide at the 3′ end of the primer hybridizes to the nucleotide nextto the target SNP site) or two or more nucleotides removed from the SNPposition. If the primer is several nucleotides removed from the targetSNP position, the only limitation is that the template sequence betweenthe 3′ end of the primer and the SNP position cannot contain anucleotide of the same type as the one to be detected, or this willcause premature termination of the extension primer. Alternatively, ifall four ddNTPs alone, with no dNTPs, are added to the reaction mixture,the primer will always be extended by only one nucleotide, correspondingto the target SNP position. In this instance, primers are designed tobind one nucleotide upstream from the SNP position (i.e., the nucleotideat the 3′ end of the primer hybridizes to the nucleotide that isimmediately adjacent to the target SNP site on the 5′ side of the targetSNP site). Extension by only one nucleotide is preferable, as itminimizes the overall mass of the extended primer, thereby increasingthe resolution of mass differences between alternative SNP nucleotides.Furthermore, mass-tagged ddNTPs can be employed in the primer extensionreactions in place of unmodified ddNTPs. This increases the massdifference between primers extended with these ddNTPs, thereby providingincreased sensitivity and accuracy, and is particularly useful fortyping heterozygous base positions. Mass-tagging also alleviates theneed for intensive sample-preparation procedures and decreases thenecessary resolving power of the mass spectrometer.

The extended primers can then be purified and analyzed by MALDI-TOF massspectrometry to determine the identity of the nucleotide present at thetarget SNP position. In one method of analysis, the products from theprimer extension reaction are combined with light absorbing crystalsthat form a matrix. The matrix is then hit with an energy source such asa laser to ionize and desorb the nucleic acid molecules into thegas-phase. The ionized molecules are then ejected into a flight tube andaccelerated down the tube towards a detector. The time between theionization event, such as a laser pulse, and collision of the moleculewith the detector is the time of flight of that molecule. The time offlight is precisely correlated with the mass-to-charge ratio (m/z) ofthe ionized molecule. Ions with smaller m/z travel down the tube fasterthan ions with larger m/z and therefore the lighter ions reach thedetector before the heavier ions. The time-of-flight is then convertedinto a corresponding, and highly precise, m/z. In this manner, SNPs canbe identified based on the slight differences in mass, and thecorresponding time of flight differences, inherent in nucleic acidmolecules having different nucleotides at a single base position. Forfurther information regarding the use of primer extension assays inconjunction with MALDI-TOF mass spectrometry for SNP genotyping, see,e.g., Wise et al., “A standard protocol for single nucleotide primerextension in the human genome using matrix-assisted laserdesorption/ionization time-of-flight mass spectrometry”, Rapid CommunMass Spectrom. 2003; 17(11):1195-202.

The following references provide further information describing massspectrometry-based methods for SNP genotyping: Bocker, “SNP and mutationdiscovery using base-specific cleavage and MALDI-TOF mass spectrometry”,Bioinformatics. 2003 July; 19 Suppl 1:144-153; Storm et al., “MALDI-TOFmass spectrometry-based SNP genotyping”, Methods Mol Biol. 2003;212:241-62; Jurinke et al., “The use of Mass ARRAY technology for highthroughput genotyping”, Adv Biochem Eng Biotechnol. 2002; 77:57-74; andJurinke et al., “Automated genotyping using the DNA MassArraytechnology”, Methods Mol Biol. 2002; 187:179-92.

SNPs can also be scored by direct DNA sequencing. A variety of automatedsequencing procedures can be utilized ((1995) Biotechniques 19:448),including sequencing by mass spectrometry (see, e.g., PCT InternationalPublication No. WO94/16101; Cohen et al., Adv. Chromatogr. 36:127-162(1996); and Griffin et al., Appl. Biochem. Biotechnol. 38:147-159(1993)). The nucleic acid sequences of the present invention enable oneof ordinary skill in the art to readily design sequencing primers forsuch automated sequencing procedures. Commercial instrumentation, suchas the Applied Biosystems 377, 3100, 3700, 3730, and 3730xl DNAAnalyzers (Foster City, Calif.), is commonly used in the art forautomated sequencing.

Other methods that can be used to genotype the SNPs of the presentinvention include single-strand conformational polymorphism (SSCP), anddenaturing gradient gel electrophoresis (DGGE) (Myers et al., Nature313:495 (1985)). SSCP identifies base differences by alteration inelectrophoretic migration of single stranded PCR products, as describedin Orita et al., Proc. Nat. Acad. Single-stranded PCR products can begenerated by heating or otherwise denaturing double stranded PCRproducts. Single-stranded nucleic acids may refold or form secondarystructures that are partially dependent on the base sequence. Thedifferent electrophoretic mobilities of single-stranded amplificationproducts are related to base-sequence differences at SNP positions. DGGEdifferentiates SNP alleles based on the different sequence-dependentstabilities and melting properties inherent in polymorphic DNA and thecorresponding differences in electrophoretic migration patterns in adenaturing gradient gel (Erlich, ed., PCR Technology, Principles andApplications for DNA Amplification, W.H. Freeman and Co, New York, 1992,Chapter 7).

Sequence-specific ribozymes (U.S. Pat. No. 5,498,531) can also be usedto score SNPs based on the development or loss of a ribozyme cleavagesite. Perfectly matched sequences can be distinguished from mismatchedsequences by nuclease cleavage digestion assays or by differences inmelting temperature. If the SNP affects a restriction enzyme cleavagesite, the SNP can be identified by alterations in restriction enzymedigestion patterns, and the corresponding changes in nucleic acidfragment lengths determined by gel electrophoresis

SNP genotyping can include the steps of, for example, collecting abiological sample from a human subject (e.g., sample of tissues, cells,fluids, secretions, etc.), isolating nucleic acids (e.g., genomic DNA,mRNA or both) from the cells of the sample, contacting the nucleic acidswith one or more primers which specifically hybridize to a region of theisolated nucleic acid containing a target SNP under conditions such thathybridization and amplification of the target nucleic acid regionoccurs, and determining the nucleotide present at the SNP position ofinterest, or, in some assays, detecting the presence or absence of anamplification product (assays can be designed so that hybridizationand/or amplification will only occur if a particular SNP allele ispresent or absent). In some assays, the size of the amplificationproduct is detected and compared to the length of a control sample; forexample, deletions and insertions can be detected by a change in size ofthe amplified product compared to a normal genotype.

SNP genotyping is useful for numerous practical applications, asdescribed below. Examples of such applications include, but are notlimited to, SNP-disease association analysis, disease predispositionscreening, disease diagnosis, disease prognosis, disease progressionmonitoring, determining therapeutic strategies based on an individual'sgenotype (“pharmacogenomics”), developing therapeutic agents based onSNP genotypes associated with a disease or likelihood of responding to adrug, stratifying a patient population for clinical trial for atreatment regimen, predicting the likelihood that an individual willexperience toxic side effects from a therapeutic agent, and humanidentification applications such as forensics.

Analysis of Genetic Association Between SNPs and Phenotypic Traits

SNP genotyping for disease diagnosis, disease predisposition screening,disease prognosis, determining drug responsiveness (pharmacogenomics),drug toxicity screening, and other uses described herein, typicallyrelies on initially establishing a genetic association between one ormore specific SNPs and the particular phenotypic traits of interest.

Different study designs may be used for genetic association studies(Modern Epidemiology, Lippincott Williams & Wilkins (1998), 609-622).Observational studies are most frequently carried out in which theresponse of the patients is not interfered with. The first type ofobservational study identifies a sample of persons in whom the suspectedcause of the disease is present and another sample of persons in whomthe suspected cause is absent, and then the frequency of development ofdisease in the two samples is compared. These sampled populations arecalled cohorts, and the study is a prospective study. The other type ofobservational study is case-control or a retrospective study. In typicalcase-control studies, samples are collected from individuals with thephenotype of interest (cases) such as certain manifestations of adisease, and from individuals without the phenotype (controls) in apopulation (target population) that conclusions are to be drawn from.Then the possible causes of the disease are investigatedretrospectively. As the time and costs of collecting samples incase-control studies are considerably less than those for prospectivestudies, case-control studies are the more commonly used study design ingenetic association studies, at least during the exploration anddiscovery stage.

In both types of observational studies, there may be potentialconfounding factors that should be taken into consideration. Confoundingfactors are those that are associated with both the real cause(s) of thedisease and the disease itself, and they include demographic informationsuch as age, gender, ethnicity as well as environmental factors. Whenconfounding factors are not matched in cases and controls in a study,and are not controlled properly, spurious association results can arise.If potential confounding factors are identified, they should becontrolled for by analysis methods explained below.

In a genetic association study, the cause of interest to be tested is acertain allele or a SNP or a combination of alleles or a haplotype fromseveral SNPs. Thus, tissue specimens (e.g., whole blood) from thesampled individuals may be collected and genomic DNA genotyped for theSNP(s) of interest. In addition to the phenotypic trait of interest,other information such as demographic (e.g., age, gender, ethnicity,etc.), clinical, and environmental information that may influence theoutcome of the trait can be collected to further characterize and definethe sample set. In many cases, these factors are known to be associatedwith diseases and/or SNP allele frequencies. There are likelygene-environment and/or gene-gene interactions as well. Analysis methodsto address gene-environment and gene-gene interactions (for example, theeffects of the presence of both susceptibility alleles at two differentgenes can be greater than the effects of the individual alleles at twogenes combined) are discussed below.

After all the relevant phenotypic and genotypic information has beenobtained, statistical analyses are carried out to determine if there isany significant correlation between the presence of an allele or agenotype with the phenotypic characteristics of an individual.Preferably, data inspection and cleaning are first performed beforecarrying out statistical tests for genetic association. Epidemiologicaland clinical data of the samples can be summarized by descriptivestatistics with tables and graphs. Data validation is preferablyperformed to check for data completion, inconsistent entries, andoutliers. Chi-squared tests and t-tests (Wilcoxon rank-sum tests ifdistributions are not normal) may then be used to check for significantdifferences between cases and controls for discrete and continuousvariables, respectively. To ensure genotyping quality, Hardy-Weinbergdisequilibrium tests can be performed on cases and controls separately.Significant deviation from Hardy-Weinberg equilibrium (HWE) in bothcases and controls for individual markers can be indicative ofgenotyping errors. If HWE is violated in a majority of markers, it isindicative of population substructure that should be furtherinvestigated. Moreover, Hardy-Weinberg disequilibrium in cases only canindicate genetic association of the markers with the disease (GeneticData Analysis, Weir B., Sinauer (1990)).

To test whether an allele of a single SNP is associated with the case orcontrol status of a phenotypic trait, one skilled in the art can compareallele frequencies in cases and controls. Standard chi-squared tests andFisher exact tests can be carried out on a 2×2 table (2 SNP alleles×2outcomes in the categorical trait of interest). To test whethergenotypes of a SNP are associated, chi-squared tests can be carried outon a 3×2 table (3 genotypes×2 outcomes). Score tests are also carriedout for genotypic association to contrast the three genotypicfrequencies (major homozygotes, heterozygotes and minor homozygotes) incases and controls, and to look for trends using 3 different modes ofinheritance, namely dominant (with contrast coefficients 2, −1, −1),additive (with contrast coefficients 1, 0, −1) and recessive (withcontrast coefficients 1, 1, −2). Odds ratios for minor versus majoralleles, and odds ratios for heterozygote and homozygote variants versusthe wild type genotypes are calculated with the desired confidencelimits, usually 95%.

In order to control for confounders and to test for interaction andeffect modifiers, stratified analyses may be performed using stratifiedfactors that are likely to be confounding, including demographicinformation such as age, ethnicity, and gender, or an interactingelement or effect modifier, such as a known major gene (e.g., APOE forAlzheimer's disease or HLA genes for autoimmune diseases), orenvironmental factors such as smoking in lung cancer. Stratifiedassociation tests may be carried out using Cochran-Mantel-Haenszel teststhat take into account the ordinal nature of genotypes with 0, 1, and 2variant alleles. Exact tests by StatXact may also be performed whencomputationally possible. Another way to adjust for confounding effectsand test for interactions is to perform stepwise multiple logisticregression analysis using statistical packages such as SAS or R.Logistic regression is a model-building technique in which the bestfitting and most parsimonious model is built to describe the relationbetween the dichotomous outcome (for instance, getting a certain diseaseor not) and a set of independent variables (for instance, genotypes ofdifferent associated genes, and the associated demographic andenvironmental factors). The most common model is one in which the logittransformation of the odds ratios is expressed as a linear combinationof the variables (main effects) and their cross-product terms(interactions) (Applied Logistic Regression, Hosmer and Lemeshow, Wiley(2000)). To test whether a certain variable or interaction issignificantly associated with the outcome, coefficients in the model arefirst estimated and then tested for statistical significance of theirdeparture from zero.

In addition to performing association tests one marker at a time,haplotype association analysis may also be performed to study a numberof markers that are closely linked together. Haplotype association testscan have better power than genotypic or allelic association tests whenthe tested markers are not the disease-causing mutations themselves butare in linkage disequilibrium with such mutations. The test will even bemore powerful if the disease is indeed caused by a combination ofalleles on a haplotype (e.g., APOE is a haplotype formed by 2 SNPs thatare very close to each other). In order to perform haplotype associationeffectively, marker-marker linkage disequilibrium measures, both D′ andR², are typically calculated for the markers within a gene to elucidatethe haplotype structure. Recent studies (Daly et al, Nature Genetics,29, 232-235, 2001) in linkage disequilibrium indicate that SNPs within agene are organized in block pattern, and a high degree of linkagedisequilibrium exists within blocks and very little linkagedisequilibrium exists between blocks. Haplotype association with thedisease status can be performed using such blocks once they have beenelucidated.

Haplotype association tests can be carried out in a similar fashion asthe allelic and genotypic association tests. Each haplotype in a gene isanalogous to an allele in a multi-allelic marker. One skilled in the artcan either compare the haplotype frequencies in cases and controls ortest genetic association with different pairs of haplotypes. It has beenproposed (Schaid et al, Am. J. Hum. Genet., 70, 425-434, 2002) thatscore tests can be done on haplotypes using the program “haplo.score”.In that method, haplotypes are first inferred by EM algorithm and scoretests are carried out with a generalized linear model (GLM) frameworkthat allows the adjustment of other factors.

An important decision in the performance of genetic association tests isthe determination of the significance level at which significantassociation can be declared when the p-value of the tests reaches thatlevel. In an exploratory analysis where positive hits will be followedup in subsequent confirmatory testing, an unadjusted p-value <0.2 (asignificance level on the lenient side), for example, may be used forgenerating hypotheses for significant association of a SNP with certainphenotypic characteristics of a disease. It is preferred that a p-value<0.05 (a significance level traditionally used in the art) is achievedin order for a SNP to be considered to have an association with adisease. It is more preferred that a p-value <0.01 (a significance levelon the stringent side) is achieved for an association to be declared.When hits are followed up in confirmatory analyses in more samples ofthe same source or in different samples from different sources,adjustment for multiple testing will be performed as to avoid excessnumber of hits while maintaining the experiment-wise error rates at0.05. While there are different methods to adjust for multiple testingto control for different kinds of error rates, a commonly used butrather conservative method is Bonferroni correction to control theexperiment-wise or family-wise error rate (Multiple comparisons andmultiple tests, Westfall et al, SAS Institute (1999)). Permutation teststo control for the false discovery rates, FDR, can be more powerful(Benjamini and Hochberg, Journal of the Royal Statistical Society,Series B 57, 1289-1300, 1995, Resampling-based Multiple Testing,Westfall and Young, Wiley (1993)). Such methods to control formultiplicity would be preferred when the tests are dependent andcontrolling for false discovery rates is sufficient as opposed tocontrolling for the experiment-wise error rates.

In replication studies using samples from different populations afterstatistically significant markers have been identified in theexploratory stage, meta-analyses can then be performed by combiningevidence of different studies (Modern Epidemiology, Lippincott Williams& Wilkins, 1998, 643-673). If available, association results known inthe art for the same SNPs can be included in the meta-analyses.

Since both genotyping and disease status classification can involveerrors, sensitivity analyses may be performed to see how odds ratios andp-values would change upon various estimates on genotyping and diseaseclassification error rates.

It has been well known that subpopulation-based sampling bias betweencases and controls can lead to spurious results in case-controlassociation studies (Ewens and Spielman, Am. J. Hum. Genet. 62, 450-458,1995) when prevalence of the disease is associated with differentsubpopulation groups. Such bias can also lead to a loss of statisticalpower in genetic association studies. To detect populationstratification, Pritchard and Rosenberg (Pritchard et al. Am. J. Hum.Gen. 1999, 65:220-228) suggested typing markers that are unlinked to thedisease and using results of association tests on those markers todetermine whether there is any population stratification. Whenstratification is detected, the genomic control (GC) method as proposedby Devlin and Roeder (Devlin et al. Biometrics 1999, 55:997-1004) can beused to adjust for the inflation of test statistics due to populationstratification. GC method is robust to changes in population structurelevels as well as being applicable to DNA pooling designs (Devlin et al.Genet. Epidem. 20001, 21:273-284).

While Pritchard's method recommended using 15-20 unlinked microsatellitemarkers, it suggested using more than 30 biallelic markers to get enoughpower to detect population stratification. For the GC method, it hasbeen shown (Bacanu et al. Am. J. Hum. Genet. 2000, 66:1933-1944) thatabout 60-70 biallelic markers are sufficient to estimate the inflationfactor for the test statistics due to population stratification. Hence,70 intergenic SNPs can be chosen in unlinked regions as indicated in agenome scan (Kehoe et al. Hum. Mol. Genet. 1999, 8:237-245).

Once individual risk factors, genetic or non-genetic, have been foundfor the predisposition to disease, the next step is to set up aclassification/prediction scheme to predict the category (for instance,disease or no-disease) that an individual will be in depending on hisgenotypes of associated SNPs and other non-genetic risk factors.Logistic regression for discrete trait and linear regression forcontinuous trait are standard techniques for such tasks (AppliedRegression Analysis, Draper and Smith, Wiley (1998)). Moreover, othertechniques can also be used for setting up classification. Suchtechniques include, but are not limited to, MART, CART, neural network,and discriminant analyses that are suitable for use in comparing theperformance of different methods (The Elements of Statistical Learning,Hastie, Tibshirani & Friedman, Springer (2002)).

Disease Diagnosis and Predisposition Screening

Information on association/correlation between genotypes anddisease-related phenotypes can be exploited in several ways. Forexample, in the case of a highly statistically significant associationbetween one or more SNPs with predisposition to a disease for whichtreatment is available, detection of such a genotype pattern in anindividual may justify immediate administration of treatment, or atleast the institution of regular monitoring of the individual. Detectionof the susceptibility alleles associated with serious disease in acouple contemplating having children may also be valuable to the couplein their reproductive decisions. In the case of a weaker but stillstatistically significant association between a SNP and a human disease,immediate therapeutic intervention or monitoring may not be justifiedafter detecting the susceptibility allele or SNP. Nevertheless, thesubject can be motivated to begin simple life-style changes (e.g., diet,exercise) that can be accomplished at little or no cost to theindividual but would confer potential benefits in reducing the risk ofdeveloping conditions for which that individual may have an increasedrisk by virtue of having the susceptibility allele(s).

The SNPs of the invention may contribute to stroke and relatedpathologies in an individual in different ways. Some polymorphisms occurwithin a protein coding sequence and contribute to disease phenotype byaffecting protein structure. Other polymorphisms occur in noncodingregions but may exert phenotypic effects indirectly via influence on,for example, replication, transcription, and/or translation. A singleSNP may affect more than one phenotypic trait. Likewise, a singlephenotypic trait may be affected by multiple SNPs in different genes.

As used herein, the terms “diagnose”, “diagnosis”, and “diagnostics”include, but are not limited to any of the following: detection of avascular disease that an individual may presently have,predisposition/susceptibility screening (i.e., determining anindividual's risk of having a stroke, such as whether an individual hasan increased or decreased risk of having a stroke in the future),determining a particular type or subclass of vascular disease or strokein an individual who has a vascular disease or who has had a stroke,confirming or reinforcing a previously made diagnosis of stroke orvascular disease, pharmacogenomic evaluation of an individual todetermine which therapeutic or preventive agent or strategy thatindividual is most likely to benefit from or to predict whether apatient is likely to benefit from a particular therapeutic or preventiveagent or strategy, predicting whether a patient is likely to experiencetoxic or other undesirable side effects from a particular therapeutic orpreventive agent or strategy, evaluating the future prognosis of anindividual who has had a stroke or who has a vascular disease, anddetermining the risk that an individual who has already had a strokewill have one or more strokes again in the future (i.e., re-occurringstrokes). Such diagnostic uses may be based on the SNPs individually orin combination or SNP haplotypes of the present invention.

Haplotypes are particularly useful in that, for example, fewer SNPs canbe genotyped to determine if a particular genomic region harbors a locusthat influences a particular phenotype, such as in linkagedisequilibrium-based SNP association analysis.

Linkage disequilibrium (LD) refers to the co-inheritance of alleles(e.g., alternative nucleotides) at two or more different SNP sites atfrequencies greater than would be expected from the separate frequenciesof occurrence of each allele in a given population. The expectedfrequency of co-occurrence of two alleles that are inheritedindependently is the frequency of the first allele multiplied by thefrequency of the second allele. Alleles that co-occur at expectedfrequencies are said to be in “linkage equilibrium”. In contrast, LDrefers to any non-random genetic association between allele(s) at two ormore different SNP sites, which is generally due to the physicalproximity of the two loci along a chromosome. LD can occur when two ormore SNPs sites are in close physical proximity to each other on a givenchromosome and therefore alleles at these SNP sites will tend to remainunseparated for multiple generations with the consequence that aparticular nucleotide (allele) at one SNP site will show a non-randomassociation with a particular nucleotide (allele) at a different SNPsite located nearby. Hence, genotyping one of the SNP sites will givealmost the same information as genotyping the other SNP site that is inLD.

Various degrees of LD can be encountered between two or more SNPs withthe result being that some SNPs are more closely associated (i.e., instronger LD) than others. Furthermore, the physical distance over whichLD extends along a chromosome differs between different regions of thegenome, and therefore the degree of physical separation between two ormore SNP sites necessary for LD to occur can differ between differentregions of the genome.

For diagnostic purposes and similar uses, if a particular SNP site isfound to be useful for determining predisposition to stroke and relatedpathologies (e.g., has a significant statistical association with thecondition and/or is recognized as a causative polymorphism for thecondition), then the skilled artisan would recognize that other SNPsites which are in LD with this SNP site would also be useful fordiagnosing the condition. Thus, polymorphisms (e.g., SNPs and/orhaplotypes) that are not the actual disease-causing (causative)polymorphisms, but are in LD with such causative polymorphisms, are alsouseful. In such instances, the genotype of the polymorphism(s) thatis/are in LD with the causative polymorphism is predictive of thegenotype of the causative polymorphism and, consequently, predictive ofthe phenotype (e.g., stroke) that is influenced by the causative SNP(s).Therefore, polymorphic markers that are in LD with causativepolymorphisms are useful as diagnostic markers, and are particularlyuseful when the actual causative polymorphism(s) is/are unknown.

Examples of polymorphisms that can be in LD with one or more causativepolymorphisms (and/or in LD with one or more polymorphisms that have asignificant statistical association with a condition) and thereforeuseful for diagnosing the same condition that the causative/associatedSNP(s) is used to diagnose, include, for example, other SNPs in the samegene, protein-coding, or mRNA transcript-coding region as thecausative/associated SNP, other SNPs in the same exon or same intron asthe causative/associated SNP, other SNPs in the same haplotype block asthe causative/associated SNP, other SNPs in the same intergenic regionas the causative/associated SNP, SNPs that are outside but near a gene(e.g., within 6 kb on either side, 5′ or 3′, of a gene boundary) thatharbors a causative/associated SNP, etc. Such useful LD SNPs can beselected from among the SNPs disclosed in Table 4, for example.

Linkage disequilibrium in the human genome is reviewed in the followingreferences: Wall et al., “Haplotype blocks and linkage disequilibrium inthe human genome,”, Nat Rev Genet. 2003 August; 4(8):587-97 (August2003); Garner et al. et al., “On selecting markers for associationstudies: patterns of linkage disequilibrium between two and threediallelic loci,”, Genet Epidemiol. 2003 January; 24(1):57-67 (January2003); Ardlie et al. et al., “Patterns of linkage disequilibrium in thehuman genome,”, Nat Rev Genet. 2002 April; 3(4):299-309 (April 2002);(erratum in Nat Rev Genet 2002 July; 3(7):566 (July 2002); and Remm etal. et al., “High-density genotyping and linkage disequilibrium in thehuman genome using chromosome 22 as a model,”; Curr Opin Chem Biol. 2002February; 6(1):24-30 (February 2002); J. B. S. Haldane, “JBS (1919) Thecombination of linkage values, and the calculation of distances betweenthe loci of linked factors,”. J Genet 8:299-309 (1919); G. Mendel, G.(1866) Versuche über Pflanzen-Hybriden. Verhandlungen desnaturforschenden Vereines in Brünn [(Proceedings of the Natural HistorySociety of Brünn)] (1866); Lewin B (1990) Genes IV, B. Lewin, ed.,Oxford University Press, New York, N.Y. USA (1990); D. L. Hartl D L andA. G. Clark A G (1989) Principles of Population Genetics 2^(nd) ed.,Sinauer Associates, Inc., Ma Sunderland, Mass., USA (1989); J. H.Gillespie J H (2004) Population Genetics: A Concise Guide. 2^(nd) ed.,Johns Hopkins University Press. (2004) USA; R. C. Lewontin, “RC (1964)The interaction of selection and linkage. I. General considerations;heterotic models,”. Genetics 49:49-67 (1964); P. G. Hoel, P G (1954)Introduction to Mathematical Statistics 2^(nd) ed., John Wiley & Sons,Inc., N.Y. New York, USA (1954); R. R. Hudson, R R “(2001) Two-locussampling distributions and their application,”. Genetics 159:1805-1817(2001); A. P. Dempster A P, N. M. Laird, D. B. N M, Rubin, “DB (1977)Maximum likelihood from incomplete data via the EM algorithm,”. J R StatSoc 39:1-48 (1977); L. Excoffier L, M. Slatkin, M “(1995)Maximum-likelihood estimation of molecular haplotype frequencies in adiploid population,”. Mol Biol Evol 12(5):921-927 (1995); D. A. TregouetDA, S. Escolano S, L. Tiret L, A. Mallet A, J. L. Golmard, J L “(2004) Anew algorithm for haplotype-based association analysis: theStochastic-EM algorithm,”. Ann Hum Genet 68(Pt 2):165-177 (2004); A. D.Long A D and C. H. Langley C H, “(1999) The power of association studiesto detect the contribution of candidate genetic loci to variation incomplex traits,”. Genome Research 9:720-731 (1999); A. Agresti, A (1990)Categorical Data Analysis., John Wiley & Sons, Inc., N.Y. New York, USA(1990); K. Lange, K (1997) Mathematical and Statistical Methods forGenetic Analysis, Springer-Verlag New York, Inc., N.Y. New York, USA(1997); The International HapMap Consortium, “(2003) The InternationalHapMap Project,”. Nature 426:789-796 (2003); The International HapMapConsortium, “(2005) A haplotype map of the human genome,”. Nature437:1299-1320 (2005); G. A. Thorisson G A, A. V. Smith A V, L. KrishnanL, L. D. Stein LD (2005), “The International HapMap Project Web Site,”.Genome Research 15:1591-1593 (2005); G. McVean, C. C. A. G, Spencer C CA, R. Chaix R (2005), “Perspectives on human genetic variation from theHapMap project,”. PLoS Genetics 1(4):413-418 (2005); J. N. Hirschhorn JN, M. J. Daly, M J “(2005) Genome-wide association studies for commondiseases and complex traits,”. Nat Genet 6:95-108 (2005); S. J. Schrodi,“S J (2005) A probabilistic approach to large-scale association scans: asemi-Bayesian method to detect disease-predisposing alleles,”. SAGMB4(1):31 (2005); W. Y. S. Wang W Y S, B. J. Barratt B J, D. G. Clayton DG, J. A. Todd, “J A (2005) Genome-wide association studies: theoreticaland practical concerns,”. Nat Rev Genet 6:109-118 (2005); J. K.Pritchard J K, M. Przeworski, “M (2001) Linkage disequilibrium inhumans: models and data,”. Am J Hum Genet 69:1-14 (2001).

As discussed above, one aspect of the present invention is the discoverythat SNPs which are in certain LD distance with the interrogated SNP canalso be used as valid markers for identifying an increased or decreasedrisks of having or developing stroke. As used herein, the term“interrogated SNP” refers to SNPs that have been found to be associatedwith an increased or decreased risk of disease using genotyping resultsand analysis, or other appropriate experimental method as exemplified inthe working examples described in this application. As used herein, theterm “LD SNP” refers to a SNP that has been characterized as a SNPassociating with an increased or decreased risk of diseases due to theirbeing in LD with the “interrogated SNP” under the methods of calculationdescribed in the application. Below, applicants describe the methods ofcalculation with which one of ordinary skilled in the art may determineif a particular SNP is in LD with an interrogated SNP. The parameter r²is commonly used in the genetics art to characterize the extent oflinkage disequilibrium between markers (Hudson, 2001). As used herein,the term “in LD with” refers to a particular SNP that is measured atabove the threshold of a parameter such as r² with an interrogated SNP.

It is now common place to directly observe genetic variants in a sampleof chromosomes obtained from a population. Suppose one has genotype dataat two genetic markers located on the same chromosome, for the markers Aand B. Further suppose that two alleles segregate at each of these twomarkers such that alleles A₁ and A₂ can be found at marker A and allelesB₁ and B₂ at marker B. Also assume that these two markers are on a humanautosome. If one is to examine a specific individual and find that theyare heterozygous at both markers, such that their two-marker genotype isA₁A₂B₁B₂, then there are two possible configurations: the individual inquestion could have the alleles A₁B₁ on one chromosome and A₂B₂ on theremaining chromosome; alternatively, the individual could have allelesA₁B₂ on one chromosome and A₂B₁ on the other. The arrangement of alleleson a chromosome is called a haplotype. In this illustration, theindividual could have haplotypes A₁B₁/A₂B₂ or A₁B₂/A₂B₁ (see Hartl andClark (1989) for a more complete description). The concept of linkageequilibrium relates the frequency of haplotypes to the allelefrequencies.

Assume that a sample of individuals is selected from a largerpopulation. Considering the two markers described above, each having twoalleles, there are four possible haplotypes: A₁B₁, A₁B₂, A₂B₁ and A₂B₂.Denote the frequencies of these four haplotypes with the followingnotation.P ₁₁=freq(A ₁ B ₁)  (1)P ₁₂=freq(A ₁ B ₂)  (2)P ₂₁=freq(A ₂ B ₁)  (3)P ₂₂=freq(A ₂ B ₂)  (4)The allele frequencies at the two markers are then the sum of differenthaplotype frequencies, it is straightforward to write down a similar setof equations relating single-marker allele frequencies to two-markerhaplotype frequencies:p ₁=freq(A ₁)=P ₁₁ +P ₁₂  (5)p ₂=freq(A ₂)=P ₂₁ +P ₂₂  (6)q ₁=freq(B ₁)=P ₁₁ +P ₂₁  (7)q ₂=freq(B ₂)=P ₁₂ +P ₂₂  (8)Note that the four haplotype frequencies and the allele frequencies ateach marker must sum to a frequency of 1.P ₁₁ +P ₁₂ +P ₂₁ +P ₂₂=1  (9)p ₁ +p ₂=1  (10)q ₁ +q ₂=1  (11)If there is no correlation between the alleles at the two markers, onewould expect that the frequency of the haplotypes would be approximatelythe product of the composite alleles. Therefore,P ₁₁ ≈p ₁ q ₁  (12)P ₁₂ ≈p ₁ q ₂  (13)P ₂₁ ≈p ₂ q ₁  (14)P ₂₂ ≈p ₂ q ₂  (15)These approximating equations (12)-(15) represent the concept of linkageequilibrium where there is independent assortment between the twomarkers—the alleles at the two markers occur together at random. Theseare represented as approximations because linkage equilibrium andlinkage disequilibrium are concepts typically thought of as propertiesof a sample of chromosomes; and as such they are susceptible tostochastic fluctuations due to the sampling process. Empirically, manypairs of genetic markers will be in linkage equilibrium, but certainlynot all pairs.

Having established the concept of linkage equilibrium above, applicantscan now describe the concept of linkage disequilibrium (LD), which isthe deviation from linkage equilibrium. Since the frequency of the A₁B₁haplotype is approximately the product of the allele frequencies for A₁and B₁ under the assumption of linkage equilibrium as statedmathematically in (12), a simple measure for the amount of departurefrom linkage equilibrium is the difference in these two quantities, D,D=P ₁₁ −p ₁ q ₁  (16)D=0 indicates perfect linkage equilibrium. Substantial departures fromD=0 indicates LD in the sample of chromosomes examined. Many propertiesof D are discussed in Lewontin (1964) including the maximum and minimumvalues that D can take. Mathematically, using basic algebra, it can beshown that D can also be written solely in terms of haplotypes:D=P ₁₁ P ₂₂ −P ₁₂ P ₂₁  (17)If one transforms D by squaring it and subsequently dividing by theproduct of the allele frequencies of A₁, A₂, B₁ and B₂, the resultingquantity, called r², is equivalent to the square of the Pearson'scorrelation coefficient commonly used in statistics (e.g. Hoel, 1954).

$\begin{matrix}{r^{2} = \frac{D^{2}}{p_{1}p_{2}q_{1}q_{2}}} & (18)\end{matrix}$

As with D, values of r² close to 0 indicate linkage equilibrium betweenthe two markers examined in the sample set. As values of r² increase,the two markers are said to be in linkage disequilibrium. The range ofvalues that r² can take are from 0 to 1. r²=1 when there is a perfectcorrelation between the alleles at the two markers.

In addition, the quantities discussed above are sample-specific. And assuch, it is necessary to formulate notation specific to the samplesstudied. In the approach discussed here, three types of samples are ofprimary interest: (i) a sample of chromosomes from individuals affectedby a disease-related phenotype (cases), (ii) a sample of chromosomesobtained from individuals not affected by the disease-related phenotype(controls), and (iii) a standard sample set used for the construction ofhaplotypes and calculation pairwise linkage disequilibrium. For theallele frequencies used in the development of the method describedbelow, an additional subscript will be added to denote either the caseor control sample sets.p _(1,cs)=freq(A ₁ in cases)  (19)p _(2,cs)=freq(A ₂ in cases)  (20)q _(1,cs)=freq(B ₁ in cases)  (21)q _(2,cs)=freq(B ₂ in cases)  (22)Similarly,p _(1,ct)=freq(A ₁ in controls)  (23)p _(2,ct)=freq(A ₂ in controls)  (24)q _(1,ct)=freq(B ₁ in controls)  (25)q _(2,ct)=freq(B ₂ in controls)  (26)

As a well-accepted sample set is necessary for robust linkagedisequilibrium calculations, data obtained from the International HapMapproject (The International HapMap Consortium 2003, 2005; Thorisson etal, 2005; McVean et al, 2005) can be used for the calculation ofpairwise r² values. Indeed, the samples genotyped for the InternationalHapMap Project were selected to be representative examples from varioushuman sub-populations with sufficient numbers of chromosomes examined todraw meaningful and robust conclusions from the patterns of geneticvariation observed. The International HapMap project website(hapmap.org) contains a description of the project, methods utilized andsamples examined. It is useful to examine empirical data to get a senseof the patterns present in such data.

Haplotype frequencies were explicit arguments in equation (18) above.However, knowing the 2-marker haplotype frequencies requires that phaseto be determined for doubly heterozygous samples. When phase is unknownin the data examined, various algorithms can be used to infer phase fromthe genotype data. This issue was discussed earlier where the doublyheterozygous individual with a 2-SNP genotype of A₁A₂B₁B₂ could have oneof two different sets of chromosomes: A₁/A₂B₂ or A₁B₂/A₂B₁. One suchalgorithm to estimate haplotype frequencies is theexpectation-maximization (EM) algorithm first formalized by Dempster etal. (1977). This algorithm is often used in genetics to infer haplotypefrequencies from genotype data (e.g., Excoffier and Slatkin (1995);Tregouet et al., (2004)). It should be noted that for the two-SNP caseexplored here, EM algorithms have very little error provided that theallele frequencies and sample sizes are not too small. The impact on r²values is typically negligible.

As correlated genetic markers share information, interrogation of SNPmarkers in LD with a disease-associated SNP marker can also havesufficient power to detect disease association (Long and Langley(1999)). The relationship between the power to directly finddisease-associated alleles and the power to indirectly detectdisease-association was investigated by Pritchard and Przeworski (2001).In a straight-forward derivation, it can be shown that the power todetect disease association indirectly at a marker locus in linkagedisequilibrium with a disease-association locus is approximately thesame as the power to detect disease-association directly at thedisease-association locus if the sample size is increased by a factor of

$\frac{1}{r^{2}}$(the reciprocal of equation 18) at the marker in comparison with thedisease-association locus.

Therefore, if one calculated the power to detect disease-associationindirectly with an experiment having N samples, then equivalent power todirectly detect disease-association (at the actualdisease-susceptibility locus) would necessitate an experiment usingapproximately r² N samples. This elementary relationship between power,sample size and linkage disequilibrium can be used to derive an r²threshold value useful in determining whether or not genotyping markersin linkage disequilibrium with a SNP marker directly associated withdisease status has enough power to indirectly detectdisease-association.

To commence a derivation of the power to detect disease-associatedmarkers through an indirect process, define the effective chromosomalsample size as

$\begin{matrix}{n = {\frac{4\; N_{cs}N_{ct}}{N_{cs} + N_{ct}}\text{;}}} & (27)\end{matrix}$where N_(cs) and N_(ct) are the numbers of diploid cases and controls,respectively. This is necessary to handle situations where the numbersof cases and controls are not equivalent. For equal case and controlsample sizes, N_(cs)=N_(ct)=N, the value of the effective number ofchromosomes is simply n=2N—as expected. Let power be calculated for asignificance level α (such that traditional P-values below α will bedeemed statistically significant). Define the standard Gaussiandistribution function as Φ(•). Mathematically,

$\begin{matrix}{{\Phi(x)} = {\frac{1}{\sqrt{2\;\pi}}{\underset{- \infty}{\int\limits^{x}}{e^{- \frac{\theta^{2}}{2}}d\;\theta}}}} & (28)\end{matrix}$Alternatively, the following error function notation (Erf) may also beused,

$\begin{matrix}{{\Phi(x)} = {\frac{1}{2}\left\lbrack {1 + {{Erf}\left( \frac{x}{\sqrt{2}} \right)}} \right\rbrack}} & (29)\end{matrix}$

For example, Φ(1.644854)=0.95. The value of r² may be derived to yield apre-specified minimum amount of power to detect disease associationthough indirect interrogation. Noting that the LD SNP marker could bethe one that is carrying the disease-association allele, therefore thatthis approach constitutes a lower-bound model where all indirect powerresults are expected to be at least as large as those interrogated.

Denote by β the error rate for not detecting truly disease-associatedmarkers. Therefore, 1−β is the classical definition of statisticalpower. Substituting the Pritchard-Pzreworski result into the samplesize, the power to detect disease association at a significance level ofα is given by the approximation

$\begin{matrix}{{1 - \beta} \cong {{\Phi\left\lbrack {\frac{{q_{1,{cs}} - q_{1,{ct}}}}{\sqrt{\frac{{q_{1,{cs}}\left( {1 - q_{1,{cs}}} \right)} + {q_{1,{ct}}\left( {t - q_{1,{ct}}} \right)}}{r^{2}n}}} - Z_{1 - {\alpha\text{/}2}}} \right\rbrack}\text{;}}} & (30)\end{matrix}$where Z_(u) is the inverse of the standard normal cumulativedistribution evaluated at u (u∈(0,1)). Z_(u)=Φ⁻¹(u), whereΦ(Φ⁻¹(u))=Φ⁻¹(Φ(u))=u. For example, setting α=0.05, and therefore1−α/2=0.975, Z_(0.975)=1.95996 is obtained. Next, setting power equal toa threshold of a minimum power of T,

$\begin{matrix}{T = {\Phi\left\lbrack {\frac{{q_{1,{cs}} - q_{1,{ct}}}}{\sqrt{\frac{{q_{1,{cs}}\left( {1 - q_{1,{cs}}} \right)} + {q_{1,{ct}}\left( {1 - q_{1,{ct}}} \right)}}{r^{2}n}}} - Z_{1 - {\alpha\text{/}2}}} \right\rbrack}} & (31)\end{matrix}$and solving for r², the following threshold r² is obtained:

$\begin{matrix}{{r_{T}^{2} = {\frac{\left\lfloor {{q_{1,{cs}}\left( {1 - q_{1,{cs}}} \right)} + {q_{1,{ct}}\left( {1 - q_{1,{ct}}} \right)}} \right\rfloor}{{n\left( {q_{1,{cs}} - q_{1,{ct}}} \right)}^{2}}\left\lbrack {{\Phi^{- 1}(T)} + Z_{1 - {\alpha\text{/}2}}} \right\rbrack}^{2}}{{Or},}} & (32) \\{r_{T}^{2} = {\frac{\left( {Z_{T} + Z_{1 - {\alpha\text{/}2}}} \right)^{2}}{n}\left\lbrack \frac{q_{1,{cs}} - \left( q_{1,{cs}} \right)^{2} + q_{1,{ct}} - \left( q_{1,{ct}} \right)^{2}}{\left( {q_{1,{cs}} - q_{1,{ct}}} \right)^{2}} \right\rbrack}} & (33)\end{matrix}$

Suppose that r² is calculated between an interrogated SNP and a numberof other SNPs with varying levels of LD with the interrogated SNP. Thethreshold value r_(T) ² is the minimum value of linkage disequilibriumbetween the interrogated SNP and the potential LD SNPs such that the LDSNP still retains a power greater or equal to T for detectingdisease-association. For example, suppose that SNP rs200 is genotyped ina case-control disease-association study and it is found to beassociated with a disease phenotype. Further suppose that the minorallele frequency in 1,000 case chromosomes was found to be 16% incontrast with a minor allele frequency of 10% in 1,000 controlchromosomes. Given those measurements one could have predicted, prior tothe experiment, that the power to detect disease association at asignificance level of 0.05 was quite high—approximately 98% using a testof allelic association. Applying equation (32) one can calculate aminimum value of r² to indirectly assess disease association assumingthat the minor allele at SNP rs200 is truly disease-predisposing for athreshold level of power. If one sets the threshold level of power to be80%, then r_(T) ²=0.489 given the same significance level and chromosomenumbers as above. Hence, any SNP with a pairwise r² value with rs200greater than 0.489 is expected to have greater than 80% power to detectthe disease association. Further, this is assuming the conservativemodel where the LD SNP is disease-associated only through linkagedisequilibrium with the interrogated SNP rs200.

The contribution or association of particular SNPs and/or SNP haplotypeswith disease phenotypes, such as stroke, enables the SNPs of the presentinvention to be used to develop superior diagnostic tests capable ofidentifying individuals who express a detectable trait, such as stroke,as the result of a specific genotype, or individuals whose genotypeplaces them at an increased or decreased risk of developing a detectabletrait at a subsequent time as compared to individuals who do not havethat genotype. As described herein, diagnostics may be based on a singleSNP or a group of SNPs. Combined detection of a plurality of SNPs (forexample, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 24, 25, 30, 32, 48, 50, 64, 96, 100, or any other number in-between,or more, of the SNPs provided in Table 1 and/or Table 2) typicallyincreases the probability of an accurate diagnosis. For example, thepresence of a single SNP known to correlate with stroke might indicate aprobability of 20% that an individual is at risk of having a stroke,whereas detection of five SNPs, each of which correlates with stroke,might indicate a probability of 80% that an individual is at risk ofhaving a stroke. To further increase the accuracy of diagnosis orpredisposition screening, analysis of the SNPs of the present inventioncan be combined with that of other polymorphisms or other risk factorsof stroke, such as disease symptoms, pathological characteristics,family history, diet, environmental factors or lifestyle factors.

It will, of course, be understood by practitioners skilled in thetreatment, prevention, or diagnosis of stroke that the present inventiongenerally does not intend to provide an absolute identification ofindividuals who are at risk (or less at risk) of having a stroke, and/orpathologies related to stroke such as other vascular diseases, butrather to indicate a certain increased (or decreased) degree orlikelihood of developing the disease (e.g., having a stroke) based onstatistically significant association results. However, this informationis extremely valuable as it can be used to, for example, initiatepreventive treatments or to allow an individual carrying one or moresignificant SNPs or SNP haplotypes to foresee warning signs such asminor clinical symptoms, or to have regularly scheduled physical examsto monitor for appearance of a condition in order to identify and begintreatment of the condition at an early stage. Particularly with diseasesthat are extremely debilitating or fatal if not treated on time, theknowledge of a potential predisposition, even if this predisposition isnot absolute, would likely contribute in a very significant manner totreatment efficacy.

The diagnostic techniques of the present invention may employ a varietyof methodologies to determine whether a test subject has a SNP or a SNPpattern associated with an increased or decreased risk of developing adetectable trait or whether the individual suffers from a detectabletrait as a result of a particular polymorphism/mutation, including, forexample, methods which enable the analysis of individual chromosomes forhaplotyping, family studies, single sperm DNA analysis, or somatichybrids. The trait analyzed using the diagnostics of the invention maybe any detectable trait that is commonly observed in pathologies anddisorders related to stroke.

Another aspect of the present invention relates to a method ofdetermining whether an individual is at risk (or less at risk) ofdeveloping one or more traits or whether an individual expresses one ormore traits as a consequence of possessing a particular trait-causing ortrait-influencing allele. These methods generally involve obtaining anucleic acid sample from an individual and assaying the nucleic acidsample to determine which nucleotide(s) is/are present at one or moreSNP positions, wherein the assayed nucleotide(s) is/are indicative of anincreased or decreased risk of developing the trait or indicative thatthe individual expresses the trait as a result of possessing aparticular trait-causing or trait-influencing allele.

In another embodiment, the SNP detection reagents of the presentinvention are used to determine whether an individual has one or moreSNP allele(s) affecting the level (e.g., the concentration of mRNA orprotein in a sample, etc.) or pattern (e.g., the kinetics of expression,rate of decomposition, stability profile, Km, Vmax, etc.) of geneexpression (collectively, the “gene response” of a cell or bodilyfluid). Such a determination can be accomplished by screening for mRNAor protein expression (e.g., by using nucleic acid arrays, RT-PCR,TaqMan assays, or mass spectrometry), identifying genes having alteredexpression in an individual, genotyping SNPs disclosed in Table 1 and/orTable 2 that could affect the expression of the genes having alteredexpression (e.g., SNPs that are in and/or around the gene(s) havingaltered expression, SNPs in regulatory/control regions, SNPs in and/oraround other genes that are involved in pathways that could affect theexpression of the gene(s) having altered expression, or all SNPs couldbe genotyped), and correlating SNP genotypes with altered geneexpression. In this manner, specific SNP alleles at particular SNP sitescan be identified that affect gene expression.

Pharmacogenomics and Therapeutics/Drug Development

The present invention provides methods for assessing thepharmacogenomics of a subject harboring particular SNP alleles orhaplotypes or diplotypes to a particular therapeutic agent orpharmaceutical compound, or to a class of such compounds.Pharmacogenomics deals with the roles which clinically significanthereditary variations (e.g., SNPs) play in the response to drugs due toaltered drug disposition and/or abnormal action in affected persons.See, e.g., Roses, Nature 405, 857-865 (2000); Gould Rothberg, NatureBiotechnology 19, 209-211 (2001); Eichelbaum, Clin. Exp. Pharmacol.Physiol. 23(10-11):983-985 (1996); and Linder, Clin. Chem. 43(2):254-266(1997). The clinical outcomes of these variations can result in severetoxicity of therapeutic drugs in certain individuals or therapeuticfailure of drugs in certain individuals as a result of individualvariation in metabolism. Thus, the SNP genotype of an individual candetermine the way a therapeutic compound acts on the body or the way thebody metabolizes the compound. For example, SNPs in drug metabolizingenzymes can affect the activity of these enzymes, which in turn canaffect both the intensity and duration of drug action, as well as drugmetabolism and clearance.

The discovery of SNPs in drug metabolizing enzymes, drug transporters,proteins for pharmaceutical agents, and other drug targets has explainedwhy some patients do not obtain the expected drug effects, show anexaggerated drug effect, or experience serious toxicity from standarddrug dosages. SNPs can be expressed in the phenotype of the extensivemetabolizer and in the phenotype of the poor metabolizer. Accordingly,SNPs may lead to allelic variants of a protein in which one or more ofthe protein functions in one population are different from those inanother population. SNPs and the encoded variant peptides thus providetargets to ascertain a genetic predisposition that can affect treatmentmodality. For example, in a ligand-based treatment, SNPs may give riseto amino terminal extracellular domains and/or other ligand-bindingregions of a receptor that are more or less active in ligand binding,thereby affecting subsequent protein activation. Accordingly, liganddosage would necessarily be modified to maximize the therapeutic effectwithin a given population containing particular SNP alleles orhaplotypes.

As an alternative to genotyping, specific variant proteins containingvariant amino acid sequences encoded by alternative SNP alleles could beidentified. Thus, pharmacogenomic characterization of an individualpermits the selection of effective compounds and effective dosages ofsuch compounds for prophylactic or therapeutic uses based on theindividual's SNP genotype, thereby enhancing and optimizing theeffectiveness of the therapy. Furthermore, the production of recombinantcells and transgenic animals containing particular SNPs/haplotypes alloweffective clinical design and testing of treatment compounds and dosageregimens. For example, transgenic animals can be produced that differonly in specific SNP alleles in a gene that is orthologous to a humandisease susceptibility gene.

Pharmacogenomic uses of the SNPs of the present invention provideseveral significant advantages for patient care, particularly intreating stroke. Pharmacogenomic characterization of an individual,based on an individual's SNP genotype, can identify those individualsunlikely to respond to treatment with a particular medication andthereby allows physicians to avoid prescribing the ineffectivemedication to those individuals. On the other hand, SNP genotyping of anindividual may enable physicians to select the appropriate medicationand dosage regimen that will be most effective based on an individual'sSNP genotype. This information increases a physician's confidence inprescribing medications and motivates patients to comply with their drugregimens. Furthermore, pharmacogenomics may identify patientspredisposed to toxicity and adverse reactions to particular drugs ordrug dosages. Adverse drug reactions lead to more than 100,000 avoidabledeaths per year in the United States alone and therefore represent asignificant cause of hospitalization and death, as well as a significanteconomic burden on the healthcare system (Pfost et. al., Trends inBiotechnology, August 2000.). Thus, pharmacogenomics based on the SNPsdisclosed herein has the potential to both save lives and reducehealthcare costs substantially.

It is also well known in the art that markers that are diagnosticallyuseful in distinguishing patients at higher risk of developing a disease(such as stroke) from those who are at a decreased risk of developingthe disease can be useful in identifying those patients who are morelikely to respond to drug treatments targeting those pathways involvinggenes where the diagnostic SNPs reside. See references Gerdes, et al.,Circulation, 2000; 101:1366-1371, Kuivenhoven, et al., N Engl J Med1998; 338:86-93, Stolarz, et al., Hypertension 2004; 44:156-162,Chartier-Harlin, et al., Hum. Mol. Genet. 1994 April; 3(4):569-74,Roses, et al., The Pharmacogenomics Journal 2006, 1-19.

In that regard, embodiments of the present invention can be very usefulin assisting clinicians to select individuals who are more likely tohave a stroke and who are therefore good candidates for receivingtherapy for the prevention or treatment of stroke, thus warrantingadministration of the above-mentioned drug treatments to suchindividuals. On the other hand, individuals who are deemed to have a lowrisk of having a stroke, using SNP markers discovered herein, can bespared the aggravation and wastefulness of the drug treatment due to thereduced benefit of such treatment in view of its cost and potential sideeffects.

Pharmacogenomics in general is discussed further in Rose et al.,“Pharmacogenetic analysis of clinically relevant genetic polymorphisms”,Methods Mol Med. 2003; 85:225-37. Pharmacogenomics as it relates toAlzheimer's disease and other neurodegenerative disorders is discussedin Cacabelos, “Pharmacogenomics for the treatment of dementia”, Ann Med.2002; 34(5):357-79, Maimone et al., “Pharmacogenomics ofneurodegenerative diseases”, Eur J Pharmacol. 2001 Feb. 9; 413(1):11-29,and Poirier, “Apolipoprotein E: a pharmacogenetic target for thetreatment of Alzheimer's disease”, Mol Diagn. 1999 December;4(4):335-41. Pharmacogenomics as it relates to cardiovascular disordersis discussed in Siest et al., “Pharmacogenomics of drugs affecting thecardiovascular system”, Clin Chem Lab Med. 2003 April; 41(4):590-9,Mukherjee et al., “Pharmacogenomics in cardiovascular diseases”, ProgCardiovasc Dis. 2002 May-June; 44(6):479-98, and Mooser et al.,“Cardiovascular pharmacogenetics in the SNP era”, J Thromb Haemost. 2003July; 1(7):1398-402. Pharmacogenomics as it relates to cancer isdiscussed in McLeod et al., “Cancer pharmacogenomics: SNPs, chips, andthe individual patient”, Cancer Invest. 2003; 21(4):630-40 and Watterset al., “Cancer pharmacogenomics: current and future applications”,Biochim Biophys Acta. 2003 Mar. 17; 1603(2):99-111.

The SNPs of the present invention also can be used to identify noveltherapeutic targets for stroke. For example, genes containing thedisease-associated variants (“variant genes”) or their products, as wellas genes or their products that are directly or indirectly regulated byor interacting with these variant genes or their products, can betargeted for the development of therapeutics that, for example, treatthe disease or prevent or delay disease onset. The therapeutics may becomposed of, for example, small molecules, proteins, protein fragmentsor peptides, antibodies, nucleic acids, or their derivatives or mimeticswhich modulate the functions or levels of the target genes or geneproducts.

The SNP-containing nucleic acid molecules disclosed herein, and theircomplementary nucleic acid molecules, may be used as antisenseconstructs to control gene expression in cells, tissues, and organisms.Antisense technology is well established in the art and extensivelyreviewed in Antisense Drug Technology: Principles, Strategies, andApplications, Crooke (ed.), Marcel Dekker, Inc.: New York (2001). Anantisense nucleic acid molecule is generally designed to becomplementary to a region of mRNA expressed by a gene so that theantisense molecule hybridizes to the mRNA and thereby blocks translationof mRNA into protein. Various classes of antisense oligonucleotides areused in the art, two of which are cleavers and blockers. Cleavers, bybinding to target RNAs, activate intracellular nucleases (e.g., RNaseHor RNase L) that cleave the target RNA. Blockers, which also bind totarget RNAs, inhibit protein translation through steric hindrance ofribosomes. Exemplary blockers include peptide nucleic acids,morpholinos, locked nucleic acids, and methylphosphonates (see, e.g.,Thompson, Drug Discovery Today, 7 (17): 912-917 (2002)). Antisenseoligonucleotides are directly useful as therapeutic agents, and are alsouseful for determining and validating gene function (e.g., in geneknock-out or knock-down experiments).

Antisense technology is further reviewed in: Lavery et al., “Antisenseand RNAi: powerful tools in drug target discovery and validation”, CurrOpin Drug Discov Devel. 2003 July; 6(4):561-9; Stephens et al.,“Antisense oligonucleotide therapy in cancer”, Curr Opin Mol Ther. 2003April; 5(2):118-22; Kurreck, “Antisense technologies. Improvementthrough novel chemical modifications”, Eur J Biochem. 2003 April;270(8):1628-44; Dias et al., “Antisense oligonucleotides: basic conceptsand mechanisms”, Mol Cancer Ther. 2002 March; 1(5):347-55; Chen,“Clinical development of antisense oligonucleotides as anti-cancertherapeutics”, Methods Mol Med. 2003; 75:621-46; Wang et al., “Antisenseanticancer oligonucleotide therapeutics”, Curr Cancer Drug Targets. 2001November; 1(3):177-96; and Bennett, “Efficiency of antisenseoligonucleotide drug discovery”, Antisense Nucleic Acid Drug Dev. 2002June; 12(3):215-24.

The SNPs of the present invention are particularly useful for designingantisense reagents that are specific for particular nucleic acidvariants. Based on the SNP information disclosed herein, antisenseoligonucleotides can be produced that specifically target mRNA moleculesthat contain one or more particular SNP nucleotides. In this manner,expression of mRNA molecules that contain one or more undesiredpolymorphisms (e.g., SNP nucleotides that lead to a defective proteinsuch as an amino acid substitution in a catalytic domain) can beinhibited or completely blocked. Thus, antisense oligonucleotides can beused to specifically bind a particular polymorphic form (e.g., a SNPallele that encodes a defective protein), thereby inhibiting translationof this form, but which do not bind an alternative polymorphic form(e.g., an alternative SNP nucleotide that encodes a protein havingnormal function).

Antisense molecules can be used to inactivate mRNA in order to inhibitgene expression and production of defective proteins. Accordingly, thesemolecules can be used to treat a disorder, such as stroke, characterizedby abnormal or undesired gene expression or expression of certaindefective proteins. This technique can involve cleavage by means ofribozymes containing nucleotide sequences complementary to one or moreregions in the mRNA that attenuate the ability of the mRNA to betranslated. Possible mRNA regions include, for example, protein-codingregions and particularly protein-coding regions corresponding tocatalytic activities, substrate/ligand binding, or other functionalactivities of a protein.

The SNPs of the present invention are also useful for designing RNAinterference reagents that specifically target nucleic acid moleculeshaving particular SNP variants. RNA interference (RNAi), also referredto as gene silencing, is based on using double-stranded RNA (dsRNA)molecules to turn genes off. When introduced into a cell, dsRNAs areprocessed by the cell into short fragments (generally about 21, 22, or23 nucleotides in length) known as small interfering RNAs (siRNAs) whichthe cell uses in a sequence-specific manner to recognize and destroycomplementary RNAs (Thompson, Drug Discovery Today, 7 (17): 912-917(2002)). Accordingly, an aspect of the present invention specificallycontemplates isolated nucleic acid molecules that are about 18-26nucleotides in length, preferably 19-25 nucleotides in length, and morepreferably 20, 21, 22, or 23 nucleotides in length, and the use of thesenucleic acid molecules for RNAi. Because RNAi molecules, includingsiRNAs, act in a sequence-specific manner, the SNPs of the presentinvention can be used to design RNAi reagents that recognize and destroynucleic acid molecules having specific SNP alleles/nucleotides (such asdeleterious alleles that lead to the production of defective proteins),while not affecting nucleic acid molecules having alternative SNPalleles (such as alleles that encode proteins having normal function).As with antisense reagents, RNAi reagents may be directly useful astherapeutic agents (e.g., for turning off defective, disease-causinggenes), and are also useful for characterizing and validating genefunction (e.g., in gene knock-out or knock-down experiments).

The following references provide a further review of RNAi: Reynolds etal., “Rational siRNA design for RNA interference”, Nat Biotechnol. 2004March; 22(3):326-30. Epub 2004 Feb. 1; Chi et al., “Genomewide view ofgene silencing by small interfering RNAs”, PNAS 100(11):6343-6346, 2003;Vickers et al., “Efficient Reduction of Target RNAs by Small InterferingRNA and RNase H-dependent Antisense Agents”, J. Biol. Chem. 278:7108-7118, 2003; Agami, “RNAi and related mechanisms and their potentialuse for therapy”, Curr Opin Chem Biol. 2002 December; 6(6):829-34;Lavery et al., “Antisense and RNAi: powerful tools in drug targetdiscovery and validation”, Curr Opin Drug Discov Devel. 2003 July;6(4):561-9; Shi, “Mammalian RNAi for the masses”, Trends Genet 2003January; 19(1):9-12), Shuey et al., “RNAi: gene-silencing in therapeuticintervention”, Drug Discovery Today 2002 October; 7(20):1040-1046;McManus et al., Nat Rev Genet 2002 October; 3(10):737-47; Xia et al.,Nat Biotechnol 2002 October; 20(10):1006-10; Plasterk et al., Curr OpinGenet Dev 2000 October; 10(5):562-7; Bosher et al., Nat Cell Biol 2000February; 2(2):E31-6; and Hunter, Curr Biol 1999 Jun. 17; 9(12):R440-2).

A subject suffering from a pathological condition, such as stroke,ascribed to a SNP may be treated so as to correct the genetic defect(see Kren et al., Proc. Natl. Acad. Sci. USA 96:10349-10354 (1999)).Such a subject can be identified by any method that can detect thepolymorphism in a biological sample drawn from the subject. Such agenetic defect may be permanently corrected by administering to such asubject a nucleic acid fragment incorporating a repair sequence thatsupplies the normal/wild-type nucleotide at the position of the SNP.This site-specific repair sequence can encompass an RNA/DNAoligonucleotide that operates to promote endogenous repair of asubject's genomic DNA. The site-specific repair sequence is administeredin an appropriate vehicle, such as a complex with polyethylenimine,encapsulated in anionic liposomes, a viral vector such as an adenovirus,or other pharmaceutical composition that promotes intracellular uptakeof the administered nucleic acid. A genetic defect leading to an inbornpathology may then be overcome, as the chimeric oligonucleotides induceincorporation of the normal sequence into the subject's genome. Uponincorporation, the normal gene product is expressed, and the replacementis propagated, thereby engendering a permanent repair and therapeuticenhancement of the clinical condition of the subject.

In cases in which a cSNP results in a variant protein that is ascribedto be the cause of, or a contributing factor to, a pathologicalcondition, a method of treating such a condition can includeadministering to a subject experiencing the pathology thewild-type/normal cognate of the variant protein. Once administered in aneffective dosing regimen, the wild-type cognate provides complementationor remediation of the pathological condition.

The invention further provides a method for identifying a compound oragent that can be used to treat or prevent stroke. The SNPs disclosedherein are useful as targets for the identification and/or developmentof therapeutic agents. A method for identifying a therapeutic agent orcompound typically includes assaying the ability of the agent orcompound to modulate the activity and/or expression of a SNP-containingnucleic acid or the encoded product and thus identifying an agent or acompound that can be used to treat a disorder characterized by undesiredactivity or expression of the SNP-containing nucleic acid or the encodedproduct. The assays can be performed in cell-based and cell-freesystems. Cell-based assays can include cells naturally expressing thenucleic acid molecules of interest or recombinant cells geneticallyengineered to express certain nucleic acid molecules.

Variant gene expression in a stroke patient can include, for example,either expression of a SNP-containing nucleic acid sequence (forinstance, a gene that contains a SNP can be transcribed into an mRNAtranscript molecule containing the SNP, which can in turn be translatedinto a variant protein) or altered expression of a normal/wild-typenucleic acid sequence due to one or more SNPs (for instance, aregulatory/control region can contain a SNP that affects the level orpattern of expression of a normal transcript).

Assays for variant gene expression can involve direct assays of nucleicacid levels (e.g., mRNA levels), expressed protein levels, or ofcollateral compounds involved in a signal pathway. Further, theexpression of genes that are up- or down-regulated in response to thesignal pathway can also be assayed. In this embodiment, the regulatoryregions of these genes can be operably linked to a reporter gene such asluciferase.

Modulators of variant gene expression can be identified in a methodwherein, for example, a cell is contacted with a candidatecompound/agent and the expression of mRNA determined. The level ofexpression of mRNA in the presence of the candidate compound is comparedto the level of expression of mRNA in the absence of the candidatecompound. The candidate compound can then be identified as a modulatorof variant gene expression based on this comparison and be used to treata disorder such as stroke that is characterized by variant geneexpression (e.g., either expression of a SNP-containing nucleic acid oraltered expression of a normal/wild-type nucleic acid molecule due toone or more SNPs that affect expression of the nucleic acid molecule)due to one or more SNPs of the present invention. When expression ofmRNA is statistically significantly greater in the presence of thecandidate compound than in its absence, the candidate compound isidentified as a stimulator of nucleic acid expression. When nucleic acidexpression is statistically significantly less in the presence of thecandidate compound than in its absence, the candidate compound isidentified as an inhibitor of nucleic acid expression.

The invention further provides methods of treatment, with the SNP orassociated nucleic acid domain (e.g., catalytic domain,ligand/substrate-binding domain, regulatory/control region, etc.) orgene, or the encoded mRNA transcript, as a target, using a compoundidentified through drug screening as a gene modulator to modulatevariant nucleic acid expression. Modulation can include eitherup-regulation (i.e., activation or agonization) or down-regulation(i.e., suppression or antagonization) of nucleic acid expression.

Expression of mRNA transcripts and encoded proteins, either wild type orvariant, may be altered in individuals with a particular SNP allele in aregulatory/control element, such as a promoter or transcription factorbinding domain, that regulates expression. In this situation, methods oftreatment and compounds can be identified, as discussed herein, thatregulate or overcome the variant regulatory/control element, therebygenerating normal, or healthy, expression levels of either the wild typeor variant protein.

The SNP-containing nucleic acid molecules of the present invention arealso useful for monitoring the effectiveness of modulating compounds onthe expression or activity of a variant gene, or encoded product, inclinical trials or in a treatment regimen. Thus, the gene expressionpattern can serve as an indicator for the continuing effectiveness oftreatment with the compound, particularly with compounds to which apatient can develop resistance, as well as an indicator for toxicities.The gene expression pattern can also serve as a marker indicative of aphysiological response of the affected cells to the compound.Accordingly, such monitoring would allow either increased administrationof the compound or the administration of alternative compounds to whichthe patient has not become resistant. Similarly, if the level of nucleicacid expression falls below a desirable level, administration of thecompound could be commensurately decreased.

In another aspect of the present invention, there is provided apharmaceutical pack comprising a therapeutic agent (e.g., a smallmolecule drug, antibody, peptide, antisense or RNAi nucleic acidmolecule, etc.) and a set of instructions for administration of thetherapeutic agent to humans diagnostically tested for one or more SNPsor SNP haplotypes provided by the present invention.

The SNPs/haplotypes of the present invention are also useful forimproving many different aspects of the drug development process. Forinstance, an aspect of the present invention includes selectingindividuals for clinical trials based on their SNP genotype. Forexample, individuals with SNP genotypes that indicate that they arelikely to positively respond to a drug can be included in the trials,whereas those individuals whose SNP genotypes indicate that they areless likely to or would not respond to the drug, or who are at risk forsuffering toxic effects or other adverse reactions, can be excluded fromthe clinical trials. This not only can improve the safety of clinicaltrials, but also can enhance the chances that the trial will demonstratestatistically significant efficacy. Furthermore, the SNPs of the presentinvention may explain why certain previously developed drugs performedpoorly in clinical trials and may help identify a subset of thepopulation that would benefit from a drug that had previously performedpoorly in clinical trials, thereby “rescuing” previously developeddrugs, and enabling the drug to be made available to a particular strokepatient population that can benefit from it.

SNPs have many important uses in drug discovery, screening, anddevelopment. A high probability exists that, for any gene/proteinselected as a potential drug target, variants of that gene/protein willexist in a patient population. Thus, determining the impact ofgene/protein variants on the selection and delivery of a therapeuticagent should be an integral aspect of the drug discovery and developmentprocess. (Jazwinska, A Trends Guide to Genetic Variation and GenomicMedicine, 2002 March; S30-S36).

Knowledge of variants (e.g., SNPs and any corresponding amino acidpolymorphisms) of a particular therapeutic target (e.g., a gene, mRNAtranscript, or protein) enables parallel screening of the variants inorder to identify therapeutic candidates (e.g., small moleculecompounds, antibodies, antisense or RNAi nucleic acid compounds, etc.)that demonstrate efficacy across variants (Rothberg, Nat Biotechnol 2001March; 19(3):209-11). Such therapeutic candidates would be expected toshow equal efficacy across a larger segment of the patient population,thereby leading to a larger potential market for the therapeuticcandidate.

Furthermore, identifying variants of a potential therapeutic targetenables the most common form of the target to be used for selection oftherapeutic candidates, thereby helping to ensure that the experimentalactivity that is observed for the selected candidates reflects the realactivity expected in the largest proportion of a patient population(Jazwinska, A Trends Guide to Genetic Variation and Genomic Medicine,2002 March; S30-S36).

Additionally, screening therapeutic candidates against all knownvariants of a target can enable the early identification of potentialtoxicities and adverse reactions relating to particular variants. Forexample, variability in drug absorption, distribution, metabolism andexcretion (ADME) caused by, for example, SNPs in therapeutic targets ordrug metabolizing genes, can be identified, and this information can beutilized during the drug development process to minimize variability indrug disposition and develop therapeutic agents that are safer across awider range of a patient population. The SNPs of the present invention,including the variant proteins and encoding polymorphic nucleic acidmolecules provided in Tables 1-2, are useful in conjunction with avariety of toxicology methods established in the art, such as those setforth in Current Protocols in Toxicology, John Wiley & Sons, Inc., N.Y.

Furthermore, therapeutic agents that target any art-known proteins (ornucleic acid molecules, either RNA or DNA) may cross-react with thevariant proteins (or polymorphic nucleic acid molecules) disclosed inTable 1, thereby significantly affecting the pharmacokinetic propertiesof the drug. Consequently, the protein variants and the SNP-containingnucleic acid molecules disclosed in Tables 1-2 are useful in developing,screening, and evaluating therapeutic agents that target correspondingart-known protein forms (or nucleic acid molecules). Additionally, asdiscussed above, knowledge of all polymorphic forms of a particular drugtarget enables the design of therapeutic agents that are effectiveagainst most or all such polymorphic forms of the drug target.

Pharmaceutical Compositions and Administration Thereof

Any of the stroke-associated proteins, and encoding nucleic acidmolecules, disclosed herein can be used as therapeutic targets (ordirectly used themselves as therapeutic compounds) for treating orpreventing stroke and related pathologies, and the present disclosureenables therapeutic compounds (e.g., small molecules, antibodies,therapeutic proteins, RNAi and antisense molecules, etc.) to bedeveloped that target (or are comprised of) any of these therapeutictargets.

In general, a therapeutic compound will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. The actualamount of the therapeutic compound of this invention, i.e., the activeingredient, will depend upon numerous factors such as the severity ofthe disease to be treated, the age and relative health of the subject,the potency of the compound used, the route and form of administration,and other factors.

Therapeutically effective amounts of therapeutic compounds may rangefrom, for example, approximately 0.01-50 mg per kilogram body weight ofthe recipient per day; preferably about 0.1-20 mg/kg/day. Thus, as anexample, for administration to a 70 kg person, the dosage range wouldmost preferably be about 7 mg to 1.4 g per day.

In general, therapeutic compounds will be administered as pharmaceuticalcompositions by any one of the following routes: oral, systemic (e.g.,transdermal, intranasal, or by suppository), or parenteral (e.g.,intramuscular, intravenous, or subcutaneous) administration. Thepreferred manner of administration is oral or parenteral using aconvenient daily dosage regimen, which can be adjusted according to thedegree of affliction. Oral compositions can take the form of tablets,pills, capsules, semisolids, powders, sustained release formulations,solutions, suspensions, elixirs, aerosols, or any other appropriatecompositions.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills, or capsules are preferred) and thebioavailability of the drug substance. Recently, pharmaceuticalformulations have been developed especially for drugs that show poorbioavailability based upon the principle that bioavailability can beincreased by increasing the surface area, i.e., decreasing particlesize. For example, U.S. Pat. No. 4,107,288 describes a pharmaceuticalformulation having particles in the size range from 10 to 1,000 nm inwhich the active material is supported on a cross-linked matrix ofmacromolecules. U.S. Pat. No. 5,145,684 describes the production of apharmaceutical formulation in which the drug substance is pulverized tonanoparticles (average particle size of 400 nm) in the presence of asurface modifier and then dispersed in a liquid medium to give apharmaceutical formulation that exhibits remarkably highbioavailability.

Pharmaceutical compositions are comprised of, in general, a therapeuticcompound in combination with at least one pharmaceutically acceptableexcipient. Acceptable excipients are non-toxic, aid administration, anddo not adversely affect the therapeutic benefit of the therapeuticcompound. Such excipients may be any solid, liquid, semi-solid or, inthe case of an aerosol composition, gaseous excipient that is generallyavailable to one skilled in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Other suitable pharmaceutical excipients and their formulations aredescribed in Remington's Pharmaceutical Sciences, edited by E. W. Martin(Mack Publishing Company, 18^(th) ed., 1990).

The amount of the therapeutic compound in a formulation can vary withinthe full range employed by those skilled in the art. Typically, theformulation will contain, on a weight percent (wt %) basis, from about0.01-99.99 wt % of the therapeutic compound based on the totalformulation, with the balance being one or more suitable pharmaceuticalexcipients. Preferably, the compound is present at a level of about 1-80wt %.

Therapeutic compounds can be administered alone or in combination withother therapeutic compounds or in combination with one or more otheractive ingredient(s). For example, an inhibitor or stimulator of astroke-associated protein can be administered in combination withanother agent that inhibits or stimulates the activity of the same or adifferent stroke-associated protein to thereby counteract the affects ofstroke.

For further information regarding pharmacology, see Current Protocols inPharmacology, John Wiley & Sons, Inc., N.Y.

Human Identification Applications

In addition to their diagnostic, risk assessment, preventive, andtherapeutic uses in stroke and related pathologies, the SNPs provided bythe present invention are also useful as human identification markersfor such applications as forensics, paternity testing, and biometrics(see, e.g., Gill, “An assessment of the utility of single nucleotidepolymorphisms (SNPs) for forensic purposes”, Int J Legal Med. 2001;114(4-5):204-10). Genetic variations in the nucleic acid sequencesbetween individuals can be used as genetic markers to identifyindividuals and to associate a biological sample with an individual.Determination of which nucleotides occupy a set of SNP positions in anindividual identifies a set of SNP markers that distinguishes theindividual. The more SNP positions that are analyzed, the lower theprobability that the set of SNPs in one individual is the same as thatin an unrelated individual. Preferably, if multiple sites are analyzed,the sites are unlinked (i.e., inherited independently). Thus, preferredsets of SNPs can be selected from among the SNPs disclosed herein, whichmay include SNPs on different chromosomes, SNPs on different chromosomearms, and/or SNPs that are dispersed over substantial distances alongthe same chromosome arm.

Furthermore, among the SNPs disclosed herein, preferred SNPs for use incertain forensic/human identification applications include SNPs locatedat degenerate codon positions (i.e., the third position in certaincodons which can be one of two or more alternative nucleotides and stillencode the same amino acid), since these SNPs do not affect the encodedprotein. SNPs that do not affect the encoded protein are expected to beunder less selective pressure and are therefore expected to be morepolymorphic in a population, which is typically an advantage forforensic/human identification applications. However, for certainforensics/human identification applications, such as predictingphenotypic characteristics (e.g., inferring ancestry or inferring one ormore physical characteristics of an individual) from a DNA sample, itmay be desirable to utilize SNPs that affect the encoded protein.

For many of the SNPs disclosed in Tables 1-2 (which are identified as“Applera” SNP source), Tables 1-2 provide SNP allele frequenciesobtained by re-sequencing the DNA of chromosomes from 39 individuals(Tables 1-2 also provide allele frequency information for “Celera”source SNPs and, where available, public SNPs from dbEST, HGBASE, and/orHGMD). The allele frequencies provided in Tables 1-2 enable these SNPsto be readily used for human identification applications. Although anySNP disclosed in Table 1 and/or Table 2 could be used for humanidentification, the closer that the frequency of the minor allele at aparticular SNP site is to 50%, the greater the ability of that SNP todiscriminate between different individuals in a population since itbecomes increasingly likely that two randomly selected individuals wouldhave different alleles at that SNP site. Using the SNP allelefrequencies provided in Tables 1-2, one of ordinary skill in the artcould readily select a subset of SNPs for which the frequency of theminor allele is, for example, at least 1%, 2%, 5%, 10%, 20%, 25%, 30%,40%, 45%, or 50%, or any other frequency in-between. Thus, since Tables1-2 provide allele frequencies based on the re-sequencing of thechromosomes from 39 individuals, a subset of SNPs could readily beselected for human identification in which the total allele count of theminor allele at a particular SNP site is, for example, at least 1, 2, 4,8, 10, 16, 20, 24, 30, 32, 36, 38, 39, 40, or any other numberin-between.

Furthermore, Tables 1-2 also provide population group (interchangeablyreferred to herein as ethnic or racial groups) information coupled withthe extensive allele frequency information. For example, the group of 39individuals whose DNA was re-sequenced was made-up of 20 Caucasians and19 African-Americans. This population group information enables furtherrefinement of SNP selection for human identification. For example,preferred SNPs for human identification can be selected from Tables 1-2that have similar allele frequencies in both the Caucasian andAfrican-American populations; thus, for example, SNPs can be selectedthat have equally high discriminatory power in both populations.Alternatively, SNPs can be selected for which there is a statisticallysignificant difference in allele frequencies between the Caucasian andAfrican-American populations (as an extreme example, a particular allelemay be observed only in either the Caucasian or the African-Americanpopulation group but not observed in the other population group); suchSNPs are useful, for example, for predicting the race/ethnicity of anunknown perpetrator from a biological sample such as a hair or bloodstain recovered at a crime scene. For a discussion of using SNPs topredict ancestry from a DNA sample, including statistical methods, seeFrudakis et al., “A Classifier for the SNP-Based Inference of Ancestry”,Journal of Forensic Sciences 2003; 48(4):771-782.

SNPs have numerous advantages over other types of polymorphic markers,such as short tandem repeats (STRs). For example, SNPs can be easilyscored and are amenable to automation, making SNPs the markers of choicefor large-scale forensic databases. SNPs are found in much greaterabundance throughout the genome than repeat polymorphisms. Populationfrequencies of two polymorphic forms can usually be determined withgreater accuracy than those of multiple polymorphic forms atmulti-allelic loci. SNPs are mutationaly more stable than repeatpolymorphisms. SNPs are not susceptible to artefacts such as stutterbands that can hinder analysis. Stutter bands are frequently encounteredwhen analyzing repeat polymorphisms, and are particularly troublesomewhen analyzing samples such as crime scene samples that may containmixtures of DNA from multiple sources. Another significant advantage ofSNP markers over STR markers is the much shorter length of nucleic acidneeded to score a SNP. For example, STR markers are generally severalhundred base pairs in length. A SNP, on the other hand, comprises asingle nucleotide, and generally a short conserved region on either sideof the SNP position for primer and/or probe binding. This makes SNPsmore amenable to typing in highly degraded or aged biological samplesthat are frequently encountered in forensic casework in which DNA may befragmented into short pieces.

SNPs also are not subject to microvariant and “off-ladder” allelesfrequently encountered when analyzing STR loci. Microvariants aredeletions or insertions within a repeat unit that change the size of theamplified DNA product so that the amplified product does not migrate atthe same rate as reference alleles with normal sized repeat units. Whenseparated by size, such as by electrophoresis on a polyacrylamide gel,microvariants do not align with a reference allelic ladder of standardsized repeat units, but rather migrate between the reference alleles.The reference allelic ladder is used for precise sizing of alleles forallele classification; therefore alleles that do not align with thereference allelic ladder lead to substantial analysis problems.Furthermore, when analyzing multi-allelic repeat polymorphisms,occasionally an allele is found that consists of more or less repeatunits than has been previously seen in the population, or more or lessrepeat alleles than are included in a reference allelic ladder. Thesealleles will migrate outside the size range of known alleles in areference allelic ladder, and therefore are referred to as “off-ladder”alleles. In extreme cases, the allele may contain so few or so manyrepeats that it migrates well out of the range of the reference allelicladder. In this situation, the allele may not even be observed, or, withmultiplex analysis, it may migrate within or close to the size range foranother locus, further confounding analysis.

SNP analysis avoids the problems of microvariants and off-ladder allelesencountered in STR analysis. Importantly, microvariants and off-ladderalleles may provide significant problems, and may be completely missed,when using analysis methods such as oligonucleotide hybridizationarrays, which utilize oligonucleotide probes specific for certain knownalleles. Furthermore, off-ladder alleles and microvariants encounteredwith STR analysis, even when correctly typed, may lead to improperstatistical analysis, since their frequencies in the population aregenerally unknown or poorly characterized, and therefore the statisticalsignificance of a matching genotype may be questionable. All theseadvantages of SNP analysis are considerable in light of the consequencesof most DNA identification cases, which may lead to life imprisonmentfor an individual, or re-association of remains to the family of adeceased individual.

DNA can be isolated from biological samples such as blood, bone, hair,saliva, or semen, and compared with the DNA from a reference source atparticular SNP positions. Multiple SNP markers can be assayedsimultaneously in order to increase the power of discrimination and thestatistical significance of a matching genotype. For example,oligonucleotide arrays can be used to genotype a large number of SNPssimultaneously. The SNPs provided by the present invention can beassayed in combination with other polymorphic genetic markers, such asother SNPs known in the art or STRs, in order to identify an individualor to associate an individual with a particular biological sample.

Furthermore, the SNPs provided by the present invention can be genotypedfor inclusion in a database of DNA genotypes, for example, a criminalDNA databank such as the FBI's Combined DNA Index System (CODIS)database. A genotype obtained from a biological sample of unknown sourcecan then be queried against the database to find a matching genotype,with the SNPs of the present invention providing nucleotide positions atwhich to compare the known and unknown DNA sequences for identity.Accordingly, the present invention provides a database comprising novelSNPs or SNP alleles of the present invention (e.g., the database cancomprise information indicating which alleles are possessed byindividual members of a population at one or more novel SNP sites of thepresent invention), such as for use in forensics, biometrics, or otherhuman identification applications. Such a database typically comprises acomputer-based system in which the SNPs or SNP alleles of the presentinvention are recorded on a computer readable medium (see the section ofthe present specification entitled “Computer-Related Embodiments”).

The SNPs of the present invention can also be assayed for use inpaternity testing. The object of paternity testing is usually todetermine whether a male is the father of a child. In most cases, themother of the child is known and thus, the mother's contribution to thechild's genotype can be traced. Paternity testing investigates whetherthe part of the child's genotype not attributable to the mother isconsistent with that of the putative father. Paternity testing can beperformed by analyzing sets of polymorphisms in the putative father andthe child, with the SNPs of the present invention providing nucleotidepositions at which to compare the putative father's and child's DNAsequences for identity. If the set of polymorphisms in the childattributable to the father does not match the set of polymorphisms ofthe putative father, it can be concluded, barring experimental error,that the putative father is not the father of the child. If the set ofpolymorphisms in the child attributable to the father match the set ofpolymorphisms of the putative father, a statistical calculation can beperformed to determine the probability of coincidental match, and aconclusion drawn as to the likelihood that the putative father is thetrue biological father of the child.

In addition to paternity testing, SNPs are also useful for other typesof kinship testing, such as for verifying familial relationships forimmigration purposes, or for cases in which an individual alleges to berelated to a deceased individual in order to claim an inheritance fromthe deceased individual, etc. For further information regarding theutility of SNPs for paternity testing and other types of kinshiptesting, including methods for statistical analysis, see Krawczak,“Informativity assessment for biallelic single nucleotidepolymorphisms”, Electrophoresis 1999 June; 20(8):1676-81.

The use of the SNPs of the present invention for human identificationfurther extends to various authentication systems, commonly referred toas biometric systems, which typically convert physical characteristicsof humans (or other organisms) into digital data. Biometric systemsinclude various technological devices that measure such uniqueanatomical or physiological characteristics as finger, thumb, or palmprints; hand geometry; vein patterning on the back of the hand; bloodvessel patterning of the retina and color and texture of the iris;facial characteristics; voice patterns; signature and typing dynamics;and DNA. Such physiological measurements can be used to verify identityand, for example, restrict or allow access based on the identification.Examples of applications for biometrics include physical area security,computer and network security, aircraft passenger check-in and boarding,financial transactions, medical records access, government benefitdistribution, voting, law enforcement, passports, visas and immigration,prisons, various military applications, and for restricting access toexpensive or dangerous items, such as automobiles or guns (see, forexample, O'Connor, Stanford Technology Law Review and U.S. Pat. No.6,119,096).

Groups of SNPs, particularly the SNPs provided by the present invention,can be typed to uniquely identify an individual for biometricapplications such as those described above. Such SNP typing can readilybe accomplished using, for example, DNA chips/arrays. Preferably, aminimally invasive means for obtaining a DNA sample is utilized. Forexample, PCR amplification enables sufficient quantities of DNA foranalysis to be obtained from buccal swabs or fingerprints, which containDNA-containing skin cells and oils that are naturally transferred duringcontact. Further information regarding techniques for using SNPs inforensic/human identification applications can be found in, for example,Current Protocols in Human Genetics, John Wiley & Sons, N.Y. (2002),14.1-14.7.

Variant Proteins, Antibodies, Vectors & Host Cells, & Uses Thereof

Variant Proteins Encoded by SNP-Containing Nucleic Acid Molecules

The present invention provides SNP-containing nucleic acid molecules,many of which encode proteins having variant amino acid sequences ascompared to the art-known (i.e., wild-type) proteins. Amino acidsequences encoded by the polymorphic nucleic acid molecules of thepresent invention are provided as SEQ ID NOS:81-160 in Table 1 and theSequence Listing. These variants will generally be referred to herein asvariant proteins/peptides/polypeptides, or polymorphicproteins/peptides/polypeptides of the present invention. The terms“protein”, “peptide”, and “polypeptide” are used herein interchangeably.

A variant protein of the present invention may be encoded by, forexample, a nonsynonymous nucleotide substitution at any one of the cSNPpositions disclosed herein. In addition, variant proteins may alsoinclude proteins whose expression, structure, and/or function is alteredby a SNP disclosed herein, such as a SNP that creates or destroys a stopcodon, a SNP that affects splicing, and a SNP in control/regulatoryelements, e.g. promoters, enhancers, or transcription factor bindingdomains.

As used herein, a protein or peptide is said to be “isolated” or“purified” when it is substantially free of cellular material orchemical precursors or other chemicals. The variant proteins of thepresent invention can be purified to homogeneity or other lower degreesof purity. The level of purification will be based on the intended use.The key feature is that the preparation allows for the desired functionof the variant protein, even if in the presence of considerable amountsof other components.

As used herein, “substantially free of cellular material” includespreparations of the variant protein having less than about 30% (by dryweight) other proteins (i.e., contaminating protein), less than about20% other proteins, less than about 10% other proteins, or less thanabout 5% other proteins. When the variant protein is recombinantlyproduced, it can also be substantially free of culture medium, i.e.,culture medium represents less than about 20% of the volume of theprotein preparation.

The language “substantially free of chemical precursors or otherchemicals” includes preparations of the variant protein in which it isseparated from chemical precursors or other chemicals that are involvedin its synthesis. In one embodiment, the language “substantially free ofchemical precursors or other chemicals” includes preparations of thevariant protein having less than about 30% (by dry weight) chemicalprecursors or other chemicals, less than about 20% chemical precursorsor other chemicals, less than about 10% chemical precursors or otherchemicals, or less than about 5% chemical precursors or other chemicals.

An isolated variant protein may be purified from cells that naturallyexpress it, purified from cells that have been altered to express it(recombinant host cells), or synthesized using known protein synthesismethods. For example, a nucleic acid molecule containing SNP(s) encodingthe variant protein can be cloned into an expression vector, theexpression vector introduced into a host cell, and the variant proteinexpressed in the host cell. The variant protein can then be isolatedfrom the cells by any appropriate purification scheme using standardprotein purification techniques. Examples of these techniques aredescribed in detail below (Sambrook and Russell, 2000, MolecularCloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y.).

The present invention provides isolated variant proteins that comprise,consist of or consist essentially of amino acid sequences that containone or more variant amino acids encoded by one or more codons whichcontain a SNP of the present invention.

Accordingly, the present invention provides variant proteins thatconsist of amino acid sequences that contain one or more amino acidpolymorphisms (or truncations or extensions due to creation ordestruction of a stop codon, respectively) encoded by the SNPs providedin Table 1 and/or Table 2. A protein consists of an amino acid sequencewhen the amino acid sequence is the entire amino acid sequence of theprotein.

The present invention further provides variant proteins that consistessentially of amino acid sequences that contain one or more amino acidpolymorphisms (or truncations or extensions due to creation ordestruction of a stop codon, respectively) encoded by the SNPs providedin Table 1 and/or Table 2. A protein consists essentially of an aminoacid sequence when such an amino acid sequence is present with only afew additional amino acid residues in the final protein.

The present invention further provides variant proteins that compriseamino acid sequences that contain one or more amino acid polymorphisms(or truncations or extensions due to creation or destruction of a stopcodon, respectively) encoded by the SNPs provided in Table 1 and/orTable 2. A protein comprises an amino acid sequence when the amino acidsequence is at least part of the final amino acid sequence of theprotein. In such a fashion, the protein may contain only the variantamino acid sequence or have additional amino acid residues, such as acontiguous encoded sequence that is naturally associated with it orheterologous amino acid residues. Such a protein can have a fewadditional amino acid residues or can comprise many more additionalamino acids. A brief description of how various types of these proteinscan be made and isolated is provided below.

The variant proteins of the present invention can be attached toheterologous sequences to form chimeric or fusion proteins. Suchchimeric and fusion proteins comprise a variant protein operativelylinked to a heterologous protein having an amino acid sequence notsubstantially homologous to the variant protein. “Operatively linked”indicates that the coding sequences for the variant protein and theheterologous protein are ligated in-frame. The heterologous protein canbe fused to the N-terminus or C-terminus of the variant protein. Inanother embodiment, the fusion protein is encoded by a fusionpolynucleotide that is synthesized by conventional techniques includingautomated DNA synthesizers. Alternatively, PCR amplification of genefragments can be carried out using anchor primers which give rise tocomplementary overhangs between two consecutive gene fragments which cansubsequently be annealed and re-amplified to generate a chimeric genesequence (see Ausubel et al., Current Protocols in Molecular Biology,1992). Moreover, many expression vectors are commercially available thatalready encode a fusion moiety (e.g., a GST protein). A variantprotein-encoding nucleic acid can be cloned into such an expressionvector such that the fusion moiety is linked in-frame to the variantprotein.

In many uses, the fusion protein does not affect the activity of thevariant protein. The fusion protein can include, but is not limited to,enzymatic fusion proteins, for example, beta-galactosidase fusions,yeast two-hybrid GAL fusions, poly-His fusions, MYC-tagged, HI-taggedand Ig fusions. Such fusion proteins, particularly poly-His fusions, canfacilitate their purification following recombinant expression. Incertain host cells (e.g., mammalian host cells), expression and/orsecretion of a protein can be increased by using a heterologous signalsequence. Fusion proteins are further described in, for example, Terpe,“Overview of tag protein fusions: from molecular and biochemicalfundamentals to commercial systems”, Appl Microbiol Biotechnol. 2003January; 60(5):523-33. Epub 2002 Nov. 7; Graddis et al., “Designingproteins that work using recombinant technologies”, Curr PharmBiotechnol. 2002 December; 3(4):285-97; and Nilsson et al., “Affinityfusion strategies for detection, purification, and immobilization ofrecombinant proteins”, Protein Expr Purif. 1997 October; 11(1):1-16.

The present invention also relates to further obvious variants of thevariant polypeptides of the present invention, such asnaturally-occurring mature forms (e.g., allelic variants), non-naturallyoccurring recombinantly-derived variants, and orthologs and paralogs ofsuch proteins that share sequence homology. Such variants can readily begenerated using art-known techniques in the fields of recombinantnucleic acid technology and protein biochemistry. It is understood,however, that variants exclude those known in the prior art before thepresent invention.

Further variants of the variant polypeptides disclosed in Table 1 cancomprise an amino acid sequence that shares at least 70-80%, 80-85%,85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identitywith an amino acid sequence disclosed in Table 1 (or a fragment thereof)and that includes a novel amino acid residue (allele) disclosed in Table1 (which is encoded by a novel SNP allele). Thus, an aspect of thepresent invention that is specifically contemplated are polypeptidesthat have a certain degree of sequence variation compared with thepolypeptide sequences shown in Table 1, but that contain a novel aminoacid residue (allele) encoded by a novel SNP allele disclosed herein. Inother words, as long as a polypeptide contains a novel amino acidresidue disclosed herein, other portions of the polypeptide that flankthe novel amino acid residue can vary to some degree from thepolypeptide sequences shown in Table 1.

Full-length pre-processed forms, as well as mature processed forms, ofproteins that comprise one of the amino acid sequences disclosed hereincan readily be identified as having complete sequence identity to one ofthe variant proteins of the present invention as well as being encodedby the same genetic locus as the variant proteins provided herein.

Orthologs of a variant peptide can readily be identified as having somedegree of significant sequence homology/identity to at least a portionof a variant peptide as well as being encoded by a gene from anotherorganism. Preferred orthologs will be isolated from non-human mammals,preferably primates, for the development of human therapeutic targetsand agents. Such orthologs can be encoded by a nucleic acid sequencethat hybridizes to a variant peptide-encoding nucleic acid moleculeunder moderate to stringent conditions depending on the degree ofrelatedness of the two organisms yielding the homologous proteins.

Variant proteins include, but are not limited to, proteins containingdeletions, additions and substitutions in the amino acid sequence causedby the SNPs of the present invention. One class of substitutions isconserved amino acid substitutions in which a given amino acid in apolypeptide is substituted for another amino acid of likecharacteristics. Typical conservative substitutions are replacements,one for another, among the aliphatic amino acids Ala, Val, Leu, and Ile;interchange of the hydroxyl residues Ser and Thr; exchange of the acidicresidues Asp and Glu; substitution between the amide residues Asn andGln; exchange of the basic residues Lys and Arg; and replacements amongthe aromatic residues Phe and Tyr. Guidance concerning which amino acidchanges are likely to be phenotypically silent are found in, forexample, Bowie et al., Science 247:1306-1310 (1990).

Variant proteins can be fully functional or can lack function in one ormore activities, e.g. ability to bind another molecule, ability tocatalyze a substrate, ability to mediate signaling, etc. Fullyfunctional variants typically contain only conservative variations orvariations in non-critical residues or in non-critical regions.Functional variants can also contain substitution of similar amino acidsthat result in no change or an insignificant change in function.Alternatively, such substitutions may positively or negatively affectfunction to some degree. Non-functional variants typically contain oneor more non-conservative amino acid substitutions, deletions,insertions, inversions, truncations or extensions, or a substitution,insertion, inversion, or deletion of a critical residue or in a criticalregion.

Amino acids that are essential for function of a protein can beidentified by methods known in the art, such as site-directedmutagenesis or alanine-scanning mutagenesis (Cunningham et al., Science244:1081-1085 (1989)), particularly using the amino acid sequence andpolymorphism information provided in Table 1. The latter procedureintroduces single alanine mutations at every residue in the molecule.The resulting mutant molecules are then tested for biological activitysuch as enzyme activity or in assays such as an in vitro proliferativeactivity. Sites that are critical for binding partner/substrate bindingcan also be determined by structural analysis such as crystallization,nuclear magnetic resonance or photoaffinity labeling (Smith et al., J.Mol. Biol. 224:899-904 (1992); de Vos et al. Science 255:306-312(1992)).

Polypeptides can contain amino acids other than the 20 amino acidscommonly referred to as the 20 naturally occurring amino acids. Further,many amino acids, including the terminal amino acids, may be modified bynatural processes, such as processing and other post-translationalmodifications, or by chemical modification techniques well known in theart. Accordingly, the variant proteins of the present invention alsoencompass derivatives or analogs in which a substituted amino acidresidue is not one encoded by the genetic code, in which a substituentgroup is included, in which the mature polypeptide is fused with anothercompound, such as a compound to increase the half-life of thepolypeptide (e.g., polyethylene glycol), or in which additional aminoacids are fused to the mature polypeptide, such as a leader or secretorysequence or a sequence for purification of the mature polypeptide or apro-protein sequence.

Known protein modifications include, but are not limited to,acetylation, acylation, ADP-ribosylation, amidation, covalent attachmentof flavin, covalent attachment of a heme moiety, covalent attachment ofa nucleotide or nucleotide derivative, covalent attachment of a lipid orlipid derivative, covalent attachment of phosphotidylinositol,cross-linking, cyclization, disulfide bond formation, demethylation,formation of covalent crosslinks, formation of cystine, formation ofpyroglutamate, formylation, gamma carboxylation, glycosylation, GPIanchor formation, hydroxylation, iodination, methylation,myristoylation, oxidation, proteolytic processing, phosphorylation,prenylation, racemization, selenoylation, sulfation, transfer-RNAmediated addition of amino acids to proteins such as arginylation, andubiquitination.

Such protein modifications are well known to those of skill in the artand have been described in great detail in the scientific literature.Several particularly common modifications, glycosylation, lipidattachment, sulfation, gamma-carboxylation of glutamic acid residues,hydroxylation and ADP-ribosylation, for instance, are described in mostbasic texts, such as Proteins—Structure and Molecular Properties, 2ndEd., T. E. Creighton, W. H. Freeman and Company, New York (1993); Wold,F., Posttranslational Covalent Modification of Proteins, B. C. Johnson,Ed., Academic Press, New York 1-12 (1983); Seifter et al., Meth.Enzymol. 182: 626-646 (1990); and Rattan et al., Ann. N. Y. Acad. Sci.663:48-62 (1992).

The present invention further provides fragments of the variant proteinsin which the fragments contain one or more amino acid sequencevariations (e.g., substitutions, or truncations or extensions due tocreation or destruction of a stop codon) encoded by one or more SNPsdisclosed herein. The fragments to which the invention pertains,however, are not to be construed as encompassing fragments that havebeen disclosed in the prior art before the present invention.

As used herein, a fragment may comprise at least about 4, 8, 10, 12, 14,16, 18, 20, 25, 30, 50, 100 (or any other number in-between) or morecontiguous amino acid residues from a variant protein, wherein at leastone amino acid residue is affected by a SNP of the present invention,e.g., a variant amino acid residue encoded by a nonsynonymous nucleotidesubstitution at a cSNP position provided by the present invention. Thevariant amino acid encoded by a cSNP may occupy any residue positionalong the sequence of the fragment. Such fragments can be chosen basedon the ability to retain one or more of the biological activities of thevariant protein or the ability to perform a function, e.g., act as animmunogen. Particularly important fragments are biologically activefragments. Such fragments will typically comprise a domain or motif of avariant protein of the present invention, e.g., active site,transmembrane domain, or ligand/substrate binding domain. Otherfragments include, but are not limited to, domain or motif-containingfragments, soluble peptide fragments, and fragments containingimmunogenic structures. Predicted domains and functional sites arereadily identifiable by computer programs well known to those of skillin the art (e.g., PROSITE analysis) (Current Protocols in ProteinScience, John Wiley & Sons, N.Y. (2002)).

Uses of Variant Proteins

The variant proteins of the present invention can be used in a varietyof ways, including but not limited to, in assays to determine thebiological activity of a variant protein, such as in a panel of multipleproteins for high-throughput screening; to raise antibodies or to elicitanother type of immune response; as a reagent (including the labeledreagent) in assays designed to quantitatively determine levels of thevariant protein (or its binding partner) in biological fluids; as amarker for cells or tissues in which it is preferentially expressed(either constitutively or at a particular stage of tissuedifferentiation or development or in a disease state); as a target forscreening for a therapeutic agent; and as a direct therapeutic agent tobe administered into a human subject. Any of the variant proteinsdisclosed herein may be developed into reagent grade or kit format forcommercialization as research products. Methods for performing the useslisted above are well known to those skilled in the art (see, e.g.,Molecular Cloning: A Laboratory Manual, Cold Spring Harbor LaboratoryPress, Sambrook and Russell, 2000, and Methods in Enzymology: Guide toMolecular Cloning Techniques, Academic Press, Berger, S. L. and A. R.Kimmel eds., 1987).

In a specific embodiment of the invention, the methods of the presentinvention include detection of one or more variant proteins disclosedherein. Variant proteins are disclosed in Table 1 and in the SequenceListing as SEQ ID NOS:81-160. Detection of such proteins can beaccomplished using, for example, antibodies, small molecule compounds,aptamers, ligands/substrates, other proteins or protein fragments, orother protein-binding agents. Preferably, protein detection agents arespecific for a variant protein of the present invention and cantherefore discriminate between a variant protein of the presentinvention and the wild-type protein or another variant form. This cangenerally be accomplished by, for example, selecting or designingdetection agents that bind to the region of a protein that differsbetween the variant and wild-type protein, such as a region of a proteinthat contains one or more amino acid substitutions that is/are encodedby a non-synonymous cSNP of the present invention, or a region of aprotein that follows a nonsense mutation-type SNP that creates a stopcodon thereby leading to a shorter polypeptide, or a region of a proteinthat follows a read-through mutation-type SNP that destroys a stop codonthereby leading to a longer polypeptide in which a portion of thepolypeptide is present in one version of the polypeptide but not theother.

In another specific aspect of the invention, the variant proteins of thepresent invention are used as targets for diagnosing stroke or fordetermining predisposition to stroke in a human (e.g., determiningwhether an individual has an increased or decreased risk of having astroke). Accordingly, the invention provides methods for detecting thepresence of, or levels of, one or more variant proteins of the presentinvention in a cell, tissue, or organism. Such methods typically involvecontacting a test sample with an agent (e.g., an antibody, smallmolecule compound, or peptide) capable of interacting with the variantprotein such that specific binding of the agent to the variant proteincan be detected. Such an assay can be provided in a single detectionformat or a multi-detection format such as an array, for example, anantibody or aptamer array (arrays for protein detection may also bereferred to as “protein chips”). The variant protein of interest can beisolated from a test sample and assayed for the presence of a variantamino acid sequence encoded by one or more SNPs disclosed by the presentinvention. The SNPs may cause changes to the protein and thecorresponding protein function/activity, such as through non-synonymoussubstitutions in protein coding regions that can lead to amino acidsubstitutions, deletions, insertions, and/or rearrangements; formationor destruction of stop codons; or alteration of control elements such aspromoters. SNPs may also cause inappropriate post-translationalmodifications.

One preferred agent for detecting a variant protein in a sample is anantibody capable of selectively binding to a variant form of the protein(antibodies are described in greater detail in the next section). Suchsamples include, for example, tissues, cells, and biological fluidsisolated from a subject, as well as tissues, cells and fluids presentwithin a subject.

In vitro methods for detection of the variant proteins associated withstroke that are disclosed herein and fragments thereof include, but arenot limited to, enzyme linked immunosorbent assays (ELISAs),radioimmunoassays (RIA), Western blots, immunoprecipitations,immunofluorescence, and protein arrays/chips (e.g., arrays of antibodiesor aptamers). For further information regarding immunoassays and relatedprotein detection methods, see Current Protocols in Immunology, JohnWiley & Sons, N.Y., and Hage, “Immunoassays”, Anal Chem. 1999 Jun. 15;71(12):294R-304R.

Additional analytic methods of detecting amino acid variants include,but are not limited to, altered electrophoretic mobility, alteredtryptic peptide digest, altered protein activity in cell-based orcell-free assay, alteration in ligand or antibody-binding pattern,altered isoelectric point, and direct amino acid sequencing.

Alternatively, variant proteins can be detected in vivo in a subject byintroducing into the subject a labeled antibody (or other type ofdetection reagent) specific for a variant protein. For example, theantibody can be labeled with a radioactive marker whose presence andlocation in a subject can be detected by standard imaging techniques.

Other uses of the variant peptides of the present invention are based onthe class or action of the protein. For example, proteins isolated fromhumans and their mammalian orthologs serve as targets for identifyingagents (e.g., small molecule drugs or antibodies) for use in therapeuticapplications, particularly for modulating a biological or pathologicalresponse in a cell or tissue that expresses the protein. Pharmaceuticalagents can be developed that modulate protein activity.

As an alternative to modulating gene expression, therapeutic compoundscan be developed that modulate protein function. For example, many SNPsdisclosed herein affect the amino acid sequence of the encoded protein(e.g., non-synonymous cSNPs and nonsense mutation-type SNPs). Suchalterations in the encoded amino acid sequence may affect proteinfunction, particularly if such amino acid sequence variations occur infunctional protein domains, such as catalytic domains, ATP-bindingdomains, or ligand/substrate binding domains. It is well established inthe art that variant proteins having amino acid sequence variations infunctional domains can cause or influence pathological conditions. Insuch instances, compounds (e.g., small molecule drugs or antibodies) canbe developed that target the variant protein and modulate (e.g., up- ordown-regulate) protein function/activity.

The therapeutic methods of the present invention further include methodsthat target one or more variant proteins of the present invention.Variant proteins can be targeted using, for example, small moleculecompounds, antibodies, aptamers, ligands/substrates, other proteins, orother protein-binding agents. Additionally, the skilled artisan willrecognize that the novel protein variants (and polymorphic nucleic acidmolecules) disclosed in Table 1 may themselves be directly used astherapeutic agents by acting as competitive inhibitors of correspondingart-known proteins (or nucleic acid molecules such as mRNA molecules).

The variant proteins of the present invention are particularly useful indrug screening assays, in cell-based or cell-free systems. Cell-basedsystems can utilize cells that naturally express the protein, a biopsyspecimen, or cell cultures. In one embodiment, cell-based assays involverecombinant host cells expressing the variant protein. Cell-free assayscan be used to detect the ability of a compound to directly bind to avariant protein or to the corresponding SNP-containing nucleic acidfragment that encodes the variant protein.

A variant protein of the present invention, as well as appropriatefragments thereof, can be used in high-throughput screening assays totest candidate compounds for the ability to bind and/or modulate theactivity of the variant protein. These candidate compounds can befurther screened against a protein having normal function (e.g., awild-type/non-variant protein) to further determine the effect of thecompound on the protein activity. Furthermore, these compounds can betested in animal or invertebrate systems to determine in vivoactivity/effectiveness. Compounds can be identified that activate(agonists) or inactivate (antagonists) the variant protein, anddifferent compounds can be identified that cause various degrees ofactivation or inactivation of the variant protein.

Further, the variant proteins can be used to screen a compound for theability to stimulate or inhibit interaction between the variant proteinand a target molecule that normally interacts with the protein. Thetarget can be a ligand, a substrate or a binding partner that theprotein normally interacts with (for example, epinephrine ornorepinephrine). Such assays typically include the steps of combiningthe variant protein with a candidate compound under conditions thatallow the variant protein, or fragment thereof, to interact with thetarget molecule, and to detect the formation of a complex between theprotein and the target or to detect the biochemical consequence of theinteraction with the variant protein and the target, such as any of theassociated effects of signal transduction.

Candidate compounds include, for example, 1) peptides such as solublepeptides, including Ig-tailed fusion peptides and members of randompeptide libraries (see, e.g., Lam et al., Nature 354:82-84 (1991);Houghten et al., Nature 354:84-86 (1991)) and combinatorialchemistry-derived molecular libraries made of D- and/or L-configurationamino acids; 2) phosphopeptides (e.g., members of random and partiallydegenerate, directed phosphopeptide libraries, see, e.g., Songyang etal., Cell 72:767-778 (1993)); 3) antibodies (e.g., polyclonal,monoclonal, humanized, anti-idiotypic, chimeric, and single chainantibodies as well as Fab, F(ab′)₂, Fab expression library fragments,and epitope-binding fragments of antibodies); and 4) small organic andinorganic molecules (e.g., molecules obtained from combinatorial andnatural product libraries).

One candidate compound is a soluble fragment of the variant protein thatcompetes for ligand binding. Other candidate compounds include mutantproteins or appropriate fragments containing mutations that affectvariant protein function and thus compete for ligand. Accordingly, afragment that competes for ligand, for example with a higher affinity,or a fragment that binds ligand but does not allow release, isencompassed by the invention.

The invention further includes other end point assays to identifycompounds that modulate (stimulate or inhibit) variant protein activity.The assays typically involve an assay of events in the signaltransduction pathway that indicate protein activity. Thus, theexpression of genes that are up or down-regulated in response to thevariant protein dependent signal cascade can be assayed. In oneembodiment, the regulatory region of such genes can be operably linkedto a marker that is easily detectable, such as luciferase.Alternatively, phosphorylation of the variant protein, or a variantprotein target, could also be measured. Any of the biological orbiochemical functions mediated by the variant protein can be used as anendpoint assay. These include all of the biochemical or biologicalevents described herein, in the references cited herein, incorporated byreference for these endpoint assay targets, and other functions known tothose of ordinary skill in the art.

Binding and/or activating compounds can also be screened by usingchimeric variant proteins in which an amino terminal extracellulardomain or parts thereof, an entire transmembrane domain or subregions,and/or the carboxyl terminal intracellular domain or parts thereof, canbe replaced by heterologous domains or subregions. For example, asubstrate-binding region can be used that interacts with a differentsubstrate than that which is normally recognized by a variant protein.Accordingly, a different set of signal transduction components isavailable as an end-point assay for activation. This allows for assaysto be performed in other than the specific host cell from which thevariant protein is derived.

The variant proteins are also useful in competition binding assays inmethods designed to discover compounds that interact with the variantprotein. Thus, a compound can be exposed to a variant protein underconditions that allow the compound to bind or to otherwise interact withthe variant protein. A binding partner, such as ligand, that normallyinteracts with the variant protein is also added to the mixture. If thetest compound interacts with the variant protein or its binding partner,it decreases the amount of complex formed or activity from the variantprotein. This type of assay is particularly useful in screening forcompounds that interact with specific regions of the variant protein(Hodgson, Bio/technology, 1992, September 10(9), 973-80).

To perform cell-free drug screening assays, it is sometimes desirable toimmobilize either the variant protein or a fragment thereof, or itstarget molecule, to facilitate separation of complexes from uncomplexedforms of one or both of the proteins, as well as to accommodateautomation of the assay. Any method for immobilizing proteins onmatrices can be used in drug screening assays. In one embodiment, afusion protein containing an added domain allows the protein to be boundto a matrix. For example, glutathione-S-transferase/¹²⁵I fusion proteinscan be adsorbed onto glutathione sepharose beads (Sigma Chemical, St.Louis, Mo.) or glutathione derivatized microtitre plates, which are thencombined with the cell lysates (e.g., ³⁵S-labeled) and a candidatecompound, such as a drug candidate, and the mixture incubated underconditions conducive to complex formation (e.g., at physiologicalconditions for salt and pH). Following incubation, the beads can bewashed to remove any unbound label, and the matrix immobilized andradiolabel determined directly, or in the supernatant after thecomplexes are dissociated. Alternatively, the complexes can bedissociated from the matrix, separated by SDS-PAGE, and the level ofbound material found in the bead fraction quantitated from the gel usingstandard electrophoretic techniques.

Either the variant protein or its target molecule can be immobilizedutilizing conjugation of biotin and streptavidin. Alternatively,antibodies reactive with the variant protein but which do not interferewith binding of the variant protein to its target molecule can bederivatized to the wells of the plate, and the variant protein trappedin the wells by antibody conjugation. Preparations of the targetmolecule and a candidate compound are incubated in the variantprotein-presenting wells and the amount of complex trapped in the wellcan be quantitated. Methods for detecting such complexes, in addition tothose described above for the GST-immobilized complexes, includeimmunodetection of complexes using antibodies reactive with the proteintarget molecule, or which are reactive with variant protein and competewith the target molecule, and enzyme-linked assays that rely ondetecting an enzymatic activity associated with the target molecule.

Modulators of variant protein activity identified according to thesedrug screening assays can be used to treat a subject with a disordermediated by the protein pathway, such as stroke. These methods oftreatment typically include the steps of administering the modulators ofprotein activity in a pharmaceutical composition to a subject in need ofsuch treatment.

The variant proteins, or fragments thereof, disclosed herein canthemselves be directly used to treat a disorder characterized by anabsence of, inappropriate, or unwanted expression or activity of thevariant protein. Accordingly, methods for treatment include the use of avariant protein disclosed herein or fragments thereof.

In yet another aspect of the invention, variant proteins can be used as“bait proteins” in a two-hybrid assay or three-hybrid assay (see, e.g.,U.S. Pat. No. 5,283,317; Zervos et al. (1993) Cell 72:223-232; Madura etal. (1993) J. Biol. Chem. 268:12046-12054; Bartel et al. (1993)Biotechniques 14:920-924; Iwabuchi et al. (1993) Oncogene 8:1693-1696;and Brent WO94/10300) to identify other proteins that bind to orinteract with the variant protein and are involved in variant proteinactivity. Such variant protein-binding proteins are also likely to beinvolved in the propagation of signals by the variant proteins orvariant protein targets as, for example, elements of a protein-mediatedsignaling pathway. Alternatively, such variant protein-binding proteinsare inhibitors of the variant protein.

The two-hybrid system is based on the modular nature of mosttranscription factors, which typically consist of separable DNA-bindingand activation domains. Briefly, the assay typically utilizes twodifferent DNA constructs. In one construct, the gene that codes for avariant protein is fused to a gene encoding the DNA binding domain of aknown transcription factor (e.g., GAL-4). In the other construct, a DNAsequence, from a library of DNA sequences, that encodes an unidentifiedprotein (“prey” or “sample”) is fused to a gene that codes for theactivation domain of the known transcription factor. If the “bait” andthe “prey” proteins are able to interact, in vivo, forming a variantprotein-dependent complex, the DNA-binding and activation domains of thetranscription factor are brought into close proximity. This proximityallows transcription of a reporter gene (e.g., LacZ) that is operablylinked to a transcriptional regulatory site responsive to thetranscription factor. Expression of the reporter gene can be detected,and cell colonies containing the functional transcription factor can beisolated and used to obtain the cloned gene that encodes the proteinthat interacts with the variant protein.

Antibodies Directed to Variant Proteins

The present invention also provides antibodies that selectively bind tothe variant proteins disclosed herein and fragments thereof. Suchantibodies may be used to quantitatively or qualitatively detect thevariant proteins of the present invention. As used herein, an antibodyselectively binds a target variant protein when it binds the variantprotein and does not significantly bind to non-variant proteins, i.e.,the antibody does not significantly bind to normal, wild-type, orart-known proteins that do not contain a variant amino acid sequence dueto one or more SNPs of the present invention (variant amino acidsequences may be due to, for example, nonsynonymous cSNPs, nonsense SNPsthat create a stop codon, thereby causing a truncation of a polypeptideor SNPs that cause read-through mutations resulting in an extension of apolypeptide).

As used herein, an antibody is defined in terms consistent with thatrecognized in the art: they are multi-subunit proteins produced by anorganism in response to an antigen challenge. The antibodies of thepresent invention include both monoclonal antibodies and polyclonalantibodies, as well as antigen-reactive proteolytic fragments of suchantibodies, such as Fab, F(ab)′₂, and Fv fragments. In addition, anantibody of the present invention further includes any of a variety ofengineered antigen-binding molecules such as a chimeric antibody (U.S.Pat. Nos. 4,816,567 and 4,816,397; Morrison et al., Proc. Natl. Acad.Sci. USA, 81:6851, 1984; Neuberger et al., Nature 312:604, 1984), ahumanized antibody (U.S. Pat. Nos. 5,693,762; 5,585,089; and 5,565,332),a single-chain Fv (U.S. Pat. No. 4,946,778; Ward et al., Nature 334:544,1989), a bispecific antibody with two binding specificities (Segal etal., J. Immunol. Methods 248:1, 2001; Carter, J. Immunol. Methods 248:7,2001), a diabody, a triabody, and a tetrabody (Todorovska et al., J.Immunol. Methods, 248:47, 2001), as well as a Fab conjugate (dimer ortrimer), and a minibody.

Many methods are known in the art for generating and/or identifyingantibodies to a given target antigen (Harlow, Antibodies, Cold SpringHarbor Press, (1989)). In general, an isolated peptide (e.g., a variantprotein of the present invention) is used as an immunogen and isadministered to a mammalian organism, such as a rat, rabbit, hamster ormouse. Either a full-length protein, an antigenic peptide fragment(e.g., a peptide fragment containing a region that varies between avariant protein and a corresponding wild-type protein), or a fusionprotein can be used. A protein used as an immunogen may benaturally-occurring, synthetic or recombinantly produced, and may beadministered in combination with an adjuvant, including but not limitedto, Freund's (complete and incomplete), mineral gels such as aluminumhydroxide, surface active substance such as lysolecithin, pluronicpolyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin,dinitrophenol, and the like.

Monoclonal antibodies can be produced by hybridoma technology (Kohlerand Milstein, Nature, 256:495, 1975), which immortalizes cells secretinga specific monoclonal antibody. The immortalized cell lines can becreated in vitro by fusing two different cell types, typicallylymphocytes, and tumor cells. The hybridoma cells may be cultivated invitro or in vivo. Additionally, fully human antibodies can be generatedby transgenic animals (He et al., J. Immunol., 169:595, 2002). Fd phageand Fd phagemid technologies may be used to generate and selectrecombinant antibodies in vitro (Hoogenboom and Chames, Immunol. Today21:371, 2000; Liu et al., J. Mol. Biol. 315:1063, 2002). Thecomplementarity-determining regions of an antibody can be identified,and synthetic peptides corresponding to such regions may be used tomediate antigen binding (U.S. Pat. No. 5,637,677).

Antibodies are preferably prepared against regions or discrete fragmentsof a variant protein containing a variant amino acid sequence ascompared to the corresponding wild-type protein (e.g., a region of avariant protein that includes an amino acid encoded by a nonsynonymouscSNP, a region affected by truncation caused by a nonsense SNP thatcreates a stop codon, or a region resulting from the destruction of astop codon due to read-through mutation caused by a SNP). Furthermore,preferred regions will include those involved in function/activityand/or protein/binding partner interaction. Such fragments can beselected on a physical property, such as fragments corresponding toregions that are located on the surface of the protein, e.g.,hydrophilic regions, or can be selected based on sequence uniqueness, orbased on the position of the variant amino acid residue(s) encoded bythe SNPs provided by the present invention. An antigenic fragment willtypically comprise at least about 8-10 contiguous amino acid residues inwhich at least one of the amino acid residues is an amino acid affectedby a SNP disclosed herein. The antigenic peptide can comprise, however,at least 12, 14, 16, 20, 25, 50, 100 (or any other number in-between) ormore amino acid residues, provided that at least one amino acid isaffected by a SNP disclosed herein.

Detection of an antibody of the present invention can be facilitated bycoupling (i.e., physically linking) the antibody or an antigen-reactivefragment thereof to a detectable substance. Detectable substancesinclude, but are not limited to, various enzymes, prosthetic groups,fluorescent materials, luminescent materials, bioluminescent materials,and radioactive materials. Examples of suitable enzymes includehorseradish peroxidase, alkaline phosphatase, β-galactosidase, oracetylcholinesterase; examples of suitable prosthetic group complexesinclude streptavidin/biotin and avidin/biotin; examples of suitablefluorescent materials include umbelliferone, fluorescein, fluoresceinisothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansylchloride or phycoerythrin; an example of a luminescent material includesluminol; examples of bioluminescent materials include luciferase,luciferin, and acquorin, and examples of suitable radioactive materialinclude ¹²⁵I, ¹³¹I, ³⁵S or ³H.

Antibodies, particularly the use of antibodies as therapeutic agents,are reviewed in: Morgan, “Antibody therapy for Alzheimer's disease”,Expert Rev Vaccines. 2003 February; 2(1):53-9; Ross et al., “Anticancerantibodies”, Am J Clin Pathol. 2003 April; 119(4):472-85; Goldenberg,“Advancing role of radiolabeled antibodies in the therapy of cancer”,Cancer Immunol Immunother. 2003 May; 52(5):281-96. Epub 2003 Mar. 11;Ross et al., “Antibody-based therapeutics in oncology”, Expert RevAnticancer Ther. 2003 February; 3(1):107-21; Cao et al., “Bispecificantibody conjugates in therapeutics”, Adv Drug Deliv Rev. 2003 Feb. 10;55(2):171-97; von Mehren et al., “Monoclonal antibody therapy forcancer”, Annu Rev Med. 2003; 54:343-69. Epub 2001 Dec. 3; Hudson et al.,“Engineered antibodies”, Nat Med. 2003 January; 9(1):129-34; Brekke etal., “Therapeutic antibodies for human diseases at the dawn of thetwenty-first century”, Nat Rev Drug Discov. 2003 January; 2(1):52-62(Erratum in: Nat Rev Drug Discov. 2003 March; 2(3):240); Houdebine,“Antibody manufacture in transgenic animals and comparisons with othersystems”, Curr Opin Biotechnol. 2002 December; 13(6):625-9; Andreakos etal., “Monoclonal antibodies in immune and inflammatory diseases”, CurrOpin Biotechnol. 2002 December; 13(6):615-20; Kellermann et al.,“Antibody discovery: the use of transgenic mice to generate humanmonoclonal antibodies for therapeutics”, Curr Opin Biotechnol. 2002December; 13(6):593-7; Pini et al., “Phage display and colony filterscreening for high-throughput selection of antibody libraries”, CombChem High Throughput Screen. 2002 November; 5(7):503-10; Batra et al.,“Pharmacokinetics and biodistribution of genetically engineeredantibodies”, Curr Opin Biotechnol. 2002 December; 13(6):603-8; andTangri et al., “Rationally engineered proteins or antibodies with absentor reduced immunogenicity”, Curr Med Chem. 2002 December; 9(24):2191-9.

Uses of Antibodies

Antibodies can be used to isolate the variant proteins of the presentinvention from a natural cell source or from recombinant host cells bystandard techniques, such as affinity chromatography orimmunoprecipitation. In addition, antibodies are useful for detectingthe presence of a variant protein of the present invention in cells ortissues to determine the pattern of expression of the variant proteinamong various tissues in an organism and over the course of normaldevelopment or disease progression. Further, antibodies can be used todetect variant protein in situ, in vitro, in a bodily fluid, or in acell lysate or supernatant in order to evaluate the amount and patternof expression. Also, antibodies can be used to assess abnormal tissuedistribution, abnormal expression during development, or expression inan abnormal condition, such as stroke. Additionally, antibody detectionof circulating fragments of the full-length variant protein can be usedto identify turnover.

Antibodies to the variant proteins of the present invention are alsouseful in pharmacogenomic analysis. Thus, antibodies against variantproteins encoded by alternative SNP alleles can be used to identifyindividuals that require modified treatment modalities.

Further, antibodies can be used to assess expression of the variantprotein in disease states such as in active stages of the disease or inan individual with a predisposition to a disease related to theprotein's function, particularly stroke. Antibodies specific for avariant protein encoded by a SNP-containing nucleic acid molecule of thepresent invention can be used to assay for the presence of the variantprotein, such as to screen for predisposition to stroke as indicated bythe presence of the variant protein.

Antibodies are also useful as diagnostic tools for evaluating thevariant proteins in conjunction with analysis by electrophoreticmobility, isoelectric point, tryptic peptide digest, and other physicalassays well known in the art.

Antibodies are also useful for tissue typing. Thus, where a specificvariant protein has been correlated with expression in a specifictissue, antibodies that are specific for this protein can be used toidentify a tissue type.

Antibodies can also be used to assess aberrant subcellular localizationof a variant protein in cells in various tissues. The diagnostic usescan be applied, not only in genetic testing, but also in monitoring atreatment modality. Accordingly, where treatment is ultimately aimed atcorrecting the expression level or the presence of variant protein oraberrant tissue distribution or developmental expression of a variantprotein, antibodies directed against the variant protein or relevantfragments can be used to monitor therapeutic efficacy.

The antibodies are also useful for inhibiting variant protein function,for example, by blocking the binding of a variant protein to a bindingpartner. These uses can also be applied in a therapeutic context inwhich treatment involves inhibiting a variant protein's function. Anantibody can be used, for example, to block or competitively inhibitbinding, thus modulating (agonizing or antagonizing) the activity of avariant protein. Antibodies can be prepared against specific variantprotein fragments containing sites required for function or against anintact variant protein that is associated with a cell or cell membrane.For in vivo administration, an antibody may be linked with an additionaltherapeutic payload such as a radionuclide, an enzyme, an immunogenicepitope, or a cytotoxic agent. Suitable cytotoxic agents include, butare not limited to, bacterial toxin such as diphtheria, and plant toxinsuch as ricin. The in vivo half-life of an antibody or a fragmentthereof may be lengthened by pegylation through conjugation topolyethylene glycol (Leong et al., Cytokine 16:106, 2001).

The invention also encompasses kits for using antibodies, such as kitsfor detecting the presence of a variant protein in a test sample. Anexemplary kit can comprise antibodies such as a labeled or labelableantibody and a compound or agent for detecting variant proteins in abiological sample; means for determining the amount, or presence/absenceof variant protein in the sample; means for comparing the amount ofvariant protein in the sample with a standard; and instructions for use.

Vectors and Host Cells

The present invention also provides vectors containing theSNP-containing nucleic acid molecules described herein. The term“vector” refers to a vehicle, preferably a nucleic acid molecule, whichcan transport a SNP-containing nucleic acid molecule. When the vector isa nucleic acid molecule, the SNP-containing nucleic acid molecule can becovalently linked to the vector nucleic acid. Such vectors include, butare not limited to, a plasmid, single or double stranded phage, a singleor double stranded RNA or DNA viral vector, or artificial chromosome,such as a BAC, PAC, YAC, or MAC.

A vector can be maintained in a host cell as an extrachromosomal elementwhere it replicates and produces additional copies of the SNP-containingnucleic acid molecules. Alternatively, the vector may integrate into thehost cell genome and produce additional copies of the SNP-containingnucleic acid molecules when the host cell replicates.

The invention provides vectors for the maintenance (cloning vectors) orvectors for expression (expression vectors) of the SNP-containingnucleic acid molecules. The vectors can function in prokaryotic oreukaryotic cells or in both (shuttle vectors).

Expression vectors typically contain cis-acting regulatory regions thatare operably linked in the vector to the SNP-containing nucleic acidmolecules such that transcription of the SNP-containing nucleic acidmolecules is allowed in a host cell. The SNP-containing nucleic acidmolecules can also be introduced into the host cell with a separatenucleic acid molecule capable of affecting transcription. Thus, thesecond nucleic acid molecule may provide a trans-acting factorinteracting with the cis-regulatory control region to allowtranscription of the SNP-containing nucleic acid molecules from thevector. Alternatively, a trans-acting factor may be supplied by the hostcell. Finally, a trans-acting factor can be produced from the vectoritself. It is understood, however, that in some embodiments,transcription and/or translation of the nucleic acid molecules can occurin a cell-free system.

The regulatory sequences to which the SNP-containing nucleic acidmolecules described herein can be operably linked include promoters fordirecting mRNA transcription. These include, but are not limited to, theleft promoter from bacteriophage λ, the lac, TRP, and TAC promoters fromE. coli, the early and late promoters from SV40, the CMV immediate earlypromoter, the adenovirus early and late promoters, and retroviruslong-terminal repeats.

In addition to control regions that promote transcription, expressionvectors may also include regions that modulate transcription, such asrepressor binding sites and enhancers. Examples include the SV40enhancer, the cytomegalovirus immediate early enhancer, polyomaenhancer, adenovirus enhancers, and retrovirus LTR enhancers.

In addition to containing sites for transcription initiation andcontrol, expression vectors can also contain sequences necessary fortranscription termination and, in the transcribed region, aribosome-binding site for translation. Other regulatory control elementsfor expression include initiation and termination codons as well aspolyadenylation signals. A person of ordinary skill in the art would beaware of the numerous regulatory sequences that are useful in expressionvectors (see, e.g., Sambrook and Russell, 2000, Molecular Cloning: ALaboratory Manual, Cold Spring Harbor Laboratory Press, Cold SpringHarbor, N.Y.).

A variety of expression vectors can be used to express a SNP-containingnucleic acid molecule. Such vectors include chromosomal, episomal, andvirus-derived vectors, for example, vectors derived from bacterialplasmids, from bacteriophage, from yeast episomes, from yeastchromosomal elements, including yeast artificial chromosomes, fromviruses such as baculoviruses, papovaviruses such as SV40, Vacciniaviruses, adenoviruses, poxviruses, pseudorabies viruses, andretroviruses. Vectors can also be derived from combinations of thesesources such as those derived from plasmid and bacteriophage geneticelements, e.g., cosmids and phagemids. Appropriate cloning andexpression vectors for prokaryotic and eukaryotic hosts are described inSambrook and Russell, 2000, Molecular Cloning: A Laboratory Manual, ColdSpring Harbor Laboratory Press, Cold Spring Harbor, N.Y.

The regulatory sequence in a vector may provide constitutive expressionin one or more host cells (e.g., tissue specific expression) or mayprovide for inducible expression in one or more cell types such as bytemperature, nutrient additive, or exogenous factor, e.g., a hormone orother ligand. A variety of vectors that provide constitutive orinducible expression of a nucleic acid sequence in prokaryotic andeukaryotic host cells are well known to those of ordinary skill in theart.

A SNP-containing nucleic acid molecule can be inserted into the vectorby methodology well-known in the art. Generally, the SNP-containingnucleic acid molecule that will ultimately be expressed is joined to anexpression vector by cleaving the SNP-containing nucleic acid moleculeand the expression vector with one or more restriction enzymes and thenligating the fragments together. Procedures for restriction enzymedigestion and ligation are well known to those of ordinary skill in theart.

The vector containing the appropriate nucleic acid molecule can beintroduced into an appropriate host cell for propagation or expressionusing well-known techniques. Bacterial host cells include, but are notlimited to, E. coli, Streptomyces, and Salmonella typhimurium.Eukaryotic host cells include, but are not limited to, yeast, insectcells such as Drosophila, animal cells such as COS and CHO cells, andplant cells.

As described herein, it may be desirable to express the variant peptideas a fusion protein. Accordingly, the invention provides fusion vectorsthat allow for the production of the variant peptides. Fusion vectorscan, for example, increase the expression of a recombinant protein,increase the solubility of the recombinant protein, and aid in thepurification of the protein by acting, for example, as a ligand foraffinity purification. A proteolytic cleavage site may be introduced atthe junction of the fusion moiety so that the desired variant peptidecan ultimately be separated from the fusion moiety. Proteolytic enzymessuitable for such use include, but are not limited to, factor Xa,thrombin, and enterokinase. Typical fusion expression vectors includepGEX (Smith et al., Gene 67:31-40 (1988)), pMAL (New England Biolabs,Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuseglutathione S-transferase (GST), maltose E binding protein, or proteinA, respectively, to the target recombinant protein. Examples of suitableinducible non-fusion E. coli expression vectors include pTrc (Amann etal., Gene 69:301-415 (1988)) and pET 11d (Studier et al., GeneExpression Technology: Methods in Enzymology 185:60-89 (1990)).

Recombinant protein expression can be maximized in a bacterial host byproviding a genetic background wherein the host cell has an impairedcapacity to proteolytically cleave the recombinant protein (Gottesman,S., Gene Expression Technology: Methods in Enzymology 185, AcademicPress, San Diego, Calif. (1990) 119-128). Alternatively, the sequence ofthe SNP-containing nucleic acid molecule of interest can be altered toprovide preferential codon usage for a specific host cell, for example,E. coli (Wada et al., Nucleic Acids Res. 20:2111-2118 (1992)).

The SNP-containing nucleic acid molecules can also be expressed byexpression vectors that are operative in yeast. Examples of vectors forexpression in yeast (e.g., S. cerevisiae) include pYepSec1 (Baldari, etal., EMBO J. 6:229-234 (1987)), pMFa (Kurjan et al., Cell30:933-943(1982)), pJRY88 (Schultz et al., Gene 54:113-123 (1987)), andpYES2 (Invitrogen Corporation, San Diego, Calif.).

The SNP-containing nucleic acid molecules can also be expressed ininsect cells using, for example, baculovirus expression vectors.Baculovirus vectors available for expression of proteins in culturedinsect cells (e.g., Sf 9 cells) include the pAc series (Smith et al.,Mol. Cell Biol. 3:2156-2165 (1983)) and the pVL series (Lucklow et al.,Virology 170:31-49 (1989)).

In certain embodiments of the invention, the SNP-containing nucleic acidmolecules described herein are expressed in mammalian cells usingmammalian expression vectors. Examples of mammalian expression vectorsinclude pCDM8 (Seed, B. Nature 329:840(1987)) and pMT2PC (Kaufman etal., EMBO J. 6:187-195 (1987)).

The invention also encompasses vectors in which the SNP-containingnucleic acid molecules described herein are cloned into the vector inreverse orientation, but operably linked to a regulatory sequence thatpermits transcription of antisense RNA. Thus, an antisense transcriptcan be produced to the SNP-containing nucleic acid sequences describedherein, including both coding and non-coding regions. Expression of thisantisense RNA is subject to each of the parameters described above inrelation to expression of the sense RNA (regulatory sequences,constitutive or inducible expression, tissue-specific expression).

The invention also relates to recombinant host cells containing thevectors described herein. Host cells therefore include, for example,prokaryotic cells, lower eukaryotic cells such as yeast, othereukaryotic cells such as insect cells, and higher eukaryotic cells suchas mammalian cells.

The recombinant host cells can be prepared by introducing the vectorconstructs described herein into the cells by techniques readilyavailable to persons of ordinary skill in the art. These include, butare not limited to, calcium phosphate transfection,DEAE-dextran-mediated transfection, cationic lipid-mediatedtransfection, electroporation, transduction, infection, lipofection, andother techniques such as those described in Sambrook and Russell, 2000,Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory,Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.).

Host cells can contain more than one vector. Thus, differentSNP-containing nucleotide sequences can be introduced in differentvectors into the same cell. Similarly, the SNP-containing nucleic acidmolecules can be introduced either alone or with other nucleic acidmolecules that are not related to the SNP-containing nucleic acidmolecules, such as those providing trans-acting factors for expressionvectors. When more than one vector is introduced into a cell, thevectors can be introduced independently, co-introduced, or joined to thenucleic acid molecule vector.

In the case of bacteriophage and viral vectors, these can be introducedinto cells as packaged or encapsulated virus by standard procedures forinfection and transduction. Viral vectors can be replication-competentor replication-defective. In the case in which viral replication isdefective, replication can occur in host cells that provide functionsthat complement the defects.

Vectors generally include selectable markers that enable the selectionof the subpopulation of cells that contain the recombinant vectorconstructs. The marker can be inserted in the same vector that containsthe SNP-containing nucleic acid molecules described herein or may be ina separate vector. Markers include, for example, tetracycline orampicillin-resistance genes for prokaryotic host cells, anddihydrofolate reductase or neomycin resistance genes for eukaryotic hostcells. However, any marker that provides selection for a phenotypictrait can be effective.

While the mature variant proteins can be produced in bacteria, yeast,mammalian cells, and other cells under the control of the appropriateregulatory sequences, cell-free transcription and translation systemscan also be used to produce these variant proteins using RNA derivedfrom the DNA constructs described herein.

Where secretion of the variant protein is desired, which is difficult toachieve with multi-transmembrane domain containing proteins such asG-protein-coupled receptors (GPCRs), appropriate secretion signals canbe incorporated into the vector. The signal sequence can be endogenousto the peptides or heterologous to these peptides.

Where the variant protein is not secreted into the medium, the proteincan be isolated from the host cell by standard disruption procedures,including freeze/thaw, sonication, mechanical disruption, use of lysingagents, and the like. The variant protein can then be recovered andpurified by well-known purification methods including, for example,ammonium sulfate precipitation, acid extraction, anion or cationicexchange chromatography, phosphocellulose chromatography,hydrophobic-interaction chromatography, affinity chromatography,hydroxylapatite chromatography, lectin chromatography, or highperformance liquid chromatography.

It is also understood that, depending upon the host cell in whichrecombinant production of the variant proteins described herein occurs,they can have various glycosylation patterns, or may benon-glycosylated, as when produced in bacteria. In addition, the variantproteins may include an initial modified methionine in some cases as aresult of a host-mediated process.

For further information regarding vectors and host cells, see CurrentProtocols in Molecular Biology, John Wiley & Sons, N.Y.

Uses of Vectors and Host Cells, and Transgenic Animals

Recombinant host cells that express the variant proteins describedherein have a variety of uses. For example, the cells are useful forproducing a variant protein that can be further purified into apreparation of desired amounts of the variant protein or fragmentsthereof. Thus, host cells containing expression vectors are useful forvariant protein production.

Host cells are also useful for conducting cell-based assays involvingthe variant protein or variant protein fragments, such as thosedescribed above as well as other formats known in the art. Thus, arecombinant host cell expressing a variant protein is useful forassaying compounds that stimulate or inhibit variant protein function.Such an ability of a compound to modulate variant protein function maynot be apparent from assays of the compound on the native/wild-typeprotein, or from cell-free assays of the compound. Recombinant hostcells are also useful for assaying functional alterations in the variantproteins as compared with a known function.

Genetically-engineered host cells can be further used to producenon-human transgenic animals. A transgenic animal is preferably anon-human mammal, for example, a rodent, such as a rat or mouse, inwhich one or more of the cells of the animal include a transgene. Atransgene is exogenous DNA containing a SNP of the present inventionwhich is integrated into the genome of a cell from which a transgenicanimal develops and which remains in the genome of the mature animal inone or more of its cell types or tissues. Such animals are useful forstudying the function of a variant protein in vivo, and identifying andevaluating modulators of variant protein activity. Other examples oftransgenic animals include, but are not limited to, non-human primates,sheep, dogs, cows, goats, chickens, and amphibians. Transgenic non-humanmammals such as cows and goats can be used to produce variant proteinswhich can be secreted in the animal's milk and then recovered.

A transgenic animal can be produced by introducing a SNP-containingnucleic acid molecule into the male pronuclei of a fertilized oocyte,e.g., by microinjection or retroviral infection, and allowing the oocyteto develop in a pseudopregnant female foster animal. Any nucleic acidmolecules that contain one or more SNPs of the present invention canpotentially be introduced as a transgene into the genome of a non-humananimal.

Any of the regulatory or other sequences useful in expression vectorscan form part of the transgenic sequence. This includes intronicsequences and polyadenylation signals, if not already included. Atissue-specific regulatory sequence(s) can be operably linked to thetransgene to direct expression of the variant protein in particularcells or tissues.

Methods for generating transgenic animals via embryo manipulation andmicroinjection, particularly animals such as mice, have becomeconventional in the art and are described in, for example, U.S. Pat.Nos. 4,736,866 and 4,870,009, both by Leder et al., U.S. Pat. No.4,873,191 by Wagner et al., and in Hogan, B., Manipulating the MouseEmbryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.,1986). Similar methods are used for production of other transgenicanimals. A transgenic founder animal can be identified based upon thepresence of the transgene in its genome and/or expression of transgenicmRNA in tissues or cells of the animals. A transgenic founder animal canthen be used to breed additional animals carrying the transgene.Moreover, transgenic animals carrying a transgene can further be bred toother transgenic animals carrying other transgenes. A transgenic animalalso includes a non-human animal in which the entire animal or tissuesin the animal have been produced using the homologously recombinant hostcells described herein.

In another embodiment, transgenic non-human animals can be producedwhich contain selected systems that allow for regulated expression ofthe transgene. One example of such a system is the cre/loxP recombinasesystem of bacteriophage P1 (Lakso et al. PNAS 89:6232-6236 (1992)).Another example of a recombinase system is the FLP recombinase system ofS. cerevisiae (O'Gorman et al. Science 251:1351-1355 (1991)). If acre/loxP recombinase system is used to regulate expression of thetransgene, animals containing transgenes encoding both the Crerecombinase and a selected protein are generally needed. Such animalscan be provided through the construction of “double” transgenic animals,e.g., by mating two transgenic animals, one containing a transgeneencoding a selected variant protein and the other containing a transgeneencoding a recombinase.

Clones of the non-human transgenic animals described herein can also beproduced according to the methods described in, for example, Wilmut, I.et al. Nature 385:810-813 (1997) and PCT International Publication Nos.WO 97/07668 and WO 97/07669. In brief, a cell (e.g., a somatic cell)from the transgenic animal can be isolated and induced to exit thegrowth cycle and enter G_(o) phase. The quiescent cell can then befused, e.g., through the use of electrical pulses, to an enucleatedoocyte from an animal of the same species from which the quiescent cellis isolated. The reconstructed oocyte is then cultured such that itdevelops to morula or blastocyst and then transferred to pseudopregnantfemale foster animal. The offspring born of this female foster animalwill be a clone of the animal from which the cell (e.g., a somatic cell)is isolated.

Transgenic animals containing recombinant cells that express the variantproteins described herein are useful for conducting the assays describedherein in an in vivo context. Accordingly, the various physiologicalfactors that are present in vivo and that could influence ligand orsubstrate binding, variant protein activation, signal transduction, orother processes or interactions, may not be evident from in vitrocell-free or cell-based assays. Thus, non-human transgenic animals ofthe present invention may be used to assay in vivo variant proteinfunction as well as the activities of a therapeutic agent or compoundthat modulates variant protein function/activity or expression. Suchanimals are also suitable for assessing the effects of null mutations(i.e., mutations that substantially or completely eliminate one or morevariant protein functions).

For further information regarding transgenic animals, see Houdebine,“Antibody manufacture in transgenic animals and comparisons with othersystems”, Curr Opin Biotechnol. 2002 December; 13(6):625-9; Petters etal., “Transgenic animals as models for human disease”, Transgenic Res.2000; 9(4-5):347-51; discussion 345-6; Wolf et al., “Use of transgenicanimals in understanding molecular mechanisms of toxicity”, J PharmPharmacol. 1998 June; 50(6):567-74; Echelard, “Recombinant proteinproduction in transgenic animals”, Curr Opin Biotechnol. 1996 October;7(5):536-40; Houdebine, “Transgenic animal bioreactors”, Transgenic Res.2000; 9(4-5):305-20; Pirity et al., “Embryonic stem cells, creatingtransgenic animals”, Methods Cell Biol. 1998; 57:279-93; and Robl etal., “Artificial chromosome vectors and expression of complex proteinsin transgenic animals”, Theriogenology. 2003 Jan. 1; 59 (1):107-13.

Examples

The following examples are offered to illustrate, but not to limit theclaimed invention.

Example One: SNPs Associated with Stroke in the Atherosclerosis Risk inCommunities (ARIC) Study

Overview

51 SNPs associated with coronary heart disease (CHD) in multipleantecedent studies (Bare et al. 2007) were analyzed to determine whetherthese SNPs are associated with incident ischemic stroke in theAtherosclerosis Risk in Communities (ARIC) study. To carry out thisanalysis, 495 validated ischemic strokes were identified from themulti-ethnic ARIC cohort of 14,215 individuals by following the cohortfor an average of 13.5 years for potential cerebrovascular events. Riskalleles for 51 SNPs were specified based on the results from at leasttwo antecedent studies in which these SNPs were associated with CHD. Asa result of this analysis, Cox proportional hazards models, adjusted forage and gender, identified three SNPs in whites/Caucasians (these termsare used herein interchangeably) and two SNPs in blacks/AfricanAmericans (these terms are used herein interchangeably) that wereassociated (p<0.05) with incident stroke and had the same risk allele asspecified by the antecedent studies. The rs11628722 polymorphism inSERPINA9 was associated with incident ischemic stroke in both whites andblacks. Thus, genetic variation in SERPINA9 was associated with incidentstroke in both whites and blacks, even after taking into accounttraditional risk factors.

Subjects and Methods

The Atherosclerosis Risk in Communities (ARIC) Study

Study participants were selected from the ARIC Study, a prospectiveinvestigation of atherosclerosis and its clinical sequelae involving15,792 individuals aged 45-64 years at recruitment (1986-1989). Subjectswere selected by probability sampling from four communities: ForsythCounty, N.C.; Jackson, Miss. (blacks only); Northwestern suburbs ofMinneapolis, Minn.; and Washington County, Md. The initial clinicalexams included a home interview to ascertain cardiovascular riskfactors, socioeconomic factors and family medical history, clinicalexamination and blood drawing for laboratory determinations. A detaileddescription of the ARIC study design and methods has been publishedelsewhere (ARIC Investigators (1989) “The Atherosclerosis Risk inCommunities (ARIC) Study: design and objectives”. American Journal ofEpidemiology 129: 687-702).

Incident Ischemic Stroke

Ischemic stroke was determined by contacting participants annually toidentify hospitalizations during the previous year, and by surveyingdischarge lists from local hospitals and death certificates from statevital statistics offices for potential cerebrovascular events (ARICInvestigators (1989) American Journal of Epidemiology 129: 687-702;Rosamond et al. (1999) Stroke 30: 736-743). Hospital records wereobtained, abstracted and classified by computer algorithm and physicianreview. Details on quality assurance for ascertainment andclassification of ischemic stroke events have been published elsewhere(Rosamond et al. (1999) Stroke 30: 736-743). Ischemic stroke events weredefined as validated definite or probable hospitalized embolic orthrombotic brain infarctions. Participants were excluded from thisanalysis if they had a positive or unknown history of prevalent stroke;transient ischemic attack/stroke symptoms or CHD at the initial visit;ethnic background other than white or black; an ethnic background ofblack but were not from Jackson, Miss.; restrictions on use of theirDNA; or missing data for any of the traditional cardiovascular orcerebrovascular risk factors. The remaining 14,215 participants werefollowed for incident ischemic stroke for a mean of 13.5 years and 495incident ischemic stroke cases were identified.

Examination and Laboratory Measures

Cardiovascular risk factors considered in this study were measured atbaseline and included age, gender, waist-to-hip ratio, diabetes,hypertension, and smoking status. The ratio of waist (umbilical level)and hip (maximum buttocks) circumference was calculated as a measure offat distribution. Diabetes was defined by a fasting glucose level ≥126mg/dl, a nonfasting glucose level ≥200 mg/dl, or a self-reportedphysician diagnosis of diabetes or use of diabetes medication. Seatedblood pressure was measured three times with a random-zerosphygmomanometer and the last two measurements were averaged. Aninterviewer-administered questionnaire was used to assess use ofantihypertensive medications. Hypertension was defined as systolic bloodpressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or current useof antihypertensive medication. Cigarette smoking status was classifiedas current or not current. The study protocol was approved by theInstitutional Review Boards of the collaborating institutions, andinformed written consent was obtained from each participant.

SNP Selection and Genotype Determination

Fifty-one functional SNPs associated with CHD in multiple antecedentstudies, other than the ARIC study, were considered in this study. Adetailed description of the antecedent studies is presented elsewhere(Bare et al., Genetics in Medicine. 2007 October; 9(10):682-9). Briefly,risk alleles for 49 SNPs were specified based on significant associationwith myocardial infarction in at least two antecedent case-controlstudies. These studies involved myocardial infarction cases and controlsrecruited by either the Cleveland Clinic Foundation Heart Center,Cleveland, Ohio (CCF) or the Genomic Resource in Arteriosclerosis at theUniversity of California, San Francisco (UCSF). All cases in these twostudies had a history of myocardial infarction and the controls did not,and all subjects were self-described, non-Hispanic Caucasians. The riskalleles for two additional SNPs were specified based on an associationwith CHD in the placebo arms of two CHD prevention trials: theCholesterol and Recurrent Events (CARE) study (Sacks et al. (1996) NewEngland Journal of Medicine 335: 1001-1009) and the West of ScotlandCoronary Prevention Study (WOSCOPS) (Packard et al. (2000) New EnglandJournal of Medicine 343: 1148-1155). One of these SNPs (rs20455 in KIF6)was significantly associated with CHD after correction for multipletesting (Iakoubova et al., Journal of the American College ofCardiology. 2008; 51:435-43). The second SNP associated with CHD in CAREand WOSCOPS was rs11666735 in FCAR (Iakoubova et al. (2006)Arteriosclerosis, Thrombosis and Vascular Biology 26: 2763-2768).

Genotyping of the 51 SNPs in the ARIC study was carried out usingPCR-based amplification of genomic DNA followed by an allele-specificoligonucleotide ligation assay similar to a previously describedprocedure (Iannone et al. (2000) Cytometry 39: 131-140).

Statistical Analyses

Agreement of genotype frequencies with Hardy-Weinberg equilibriumexpectations was tested separately in whites and blacks using a χ²goodness-of-fit test in non-cases, stratified by ethnicity. Deviationfrom Hardy-Weinberg equilibrium was determined by a p-value less than0.05. Cox proportional hazards models were used to model time toincident ischemic stroke. The follow-up time interval was defined as thetime between the initial clinical visit and the end of follow-up, whichfor cases was the date of the first ischemic stroke event and fornon-cases was Dec. 31, 2002, the date of death, or the date of lastcontact if lost to follow-up. Each model was evaluated separately inwhites and blacks and included a given SNP (modeled as the additiveeffect of the pre-specified risk allele), age and gender. Additionalrisk factors evaluated as potential confounders in the Cox proportionalhazards models included waist-to-hip ratio, diabetes, hypertension, andsmoking status (Folsom et al., (1999) Diabetes Care 22: 1077-1083). SNPsand risk factors were assessed for statistical significance in themodels by the Wald statistic. A two-sided p-value of 0.05 was used toassess statistical significance with ischemic stroke and no attempt wasmade to adjust for multiple comparisons within this study.

Results

Race-specific proportions, means and standard deviations for thetraditional risk factors are presented in Table 5. Mean values andproportions differed significantly (p<0.03) between incident ischemicstroke cases and non-cases for all risk factors.

Three SNPs in whites (in SERPINA9, PALLD and IER2) and two SNPs inblacks (in SERPINA9 and EXOD1) were associated (p≤0.05) with ischemicstroke, after adjusting for age and gender, and had the same risk alleleas specified by the antecedent studies (Table 6, Model 1). Oneadditional SNP in EIF2AK2 was associated with ischemic stroke in whites,but the risk allele in the ARIC study differed from the risk alleleidentified in the antecedent CHD studies. The rs11628722 polymorphism inSERPINA9 was associated with incident ischemic stroke in bothethnicities (whites HRR=1.31, 95% CI: 1.00-1.70; blacks HRR=1.26, 95%CI: 1.03-1.53).

For the four SNPs that were associated in either ethnic group,traditional cardiovascular risk factors were included in the Coxproportional hazards models to evaluate possible confounding. Theobserved hazards ratios were essentially unchanged with addition ofthese risk factors to the prediction models (Table 6, Model 2).

Discussion

This study investigated whether 51 putative functional SNPs associatedwith CHD in multiple antecedent studies predict ischemic stroke amongwhite and black individuals from the large prospective ARIC study. ThreeSNPs in whites and two SNPs in blacks were associated with incidentischemic stroke, even after taking into account established riskfactors. The rs11628722 polymorphism in SERPINA9 was associated withischemic stroke in both whites and blacks from the ARIC study.

It is noteworthy that the association between SERPINA9 and stroke wasobserved in both whites and blacks in this study. This SNP has beenassociated with myocardial infarction in two case-control studies andthis study shows an association with stroke in both whites and blacksfrom the ARIC study. SERPINA9 is a member of clade A of the largesuperfamily of serine peptidase inhibitors known as serpins. Serpins areprotease inhibitors that use a conformational change to inhibit targetenzymes, and are involved in many cellular processes, such ascoagulation, fibrinolysis, complement fixation, matrix remodeling andapoptosis (Law et al. (2006) Genome Biology 7: 216). A recent studyindicated that SERPINA9 was significantly upregulated in the hippocampaltissues from Alzheimer's disease transgenic mice versus age-matchedcontrols (Jee et al (2006) Neurochemistry Research 31: 1035-1044). Thisstudy suggests that SERPINA9 may also be expressed in the human brain,consistent with the findings described herein of an association betweenpolymorphic variation in this gene and ischemic stroke.

In addition to SERPINA9, polymorphisms in palladin (PALLD) and immediateearly response 2 (IER2) were associated with ischemic stroke in whitesand a polymorphism in exonuclease domain containing 1 (EXOD1) wasassociated in blacks. PALLD encodes a component of the cytoskeleton thatcontrols cell shape and motility. Vascular remodeling may lead toatherosclerosis, and the shape and cytoskeletal organization ofendothelial cells is an important part of this process. Mechanicalstress and strain also plays a role in atherosclerotic vascularremodeling and immediate early response genes have been shown to mediatethe mechanical stress-induced pathological process in the blood vessel(Liu et al. (1999) Critical Reviews in Biomedical Engineering 27:75-148). Although little is known about EXOD1, exonucleases have beenshown to play a role in both myocardial infarction and stroke. Giventheir functional roles, PALLD, IER2 and EXOD1 potentially play a role inthe atherosclerotic pathway. Additionally, PALLD, IER2 and EXOD1 are allexpressed in the heart and brain.

A strength of this study is the prospective cohort design. The largesample size allows for the assessment of exposures (e.g. geneticfactors) of modest effect. All analyses for this study were performedseparately in whites and blacks.

Thus, a small subset of gene variants previously associated with CHD inantecedent studies were found to also be associated with incidentischemic stroke in ARIC. In particular, SERPINA9 was associated withstroke in both whites and blacks and this association does not appear tobe mediated by traditional risk factors.

Supplemental Analysis of SNPs in the ARIC Study

In a further analysis of the 51 SNPs in the ARIC participants, SNPs thatpredict ischemic stroke risk were identified by Cox proportional hazardanalysis and included SNPs with a two-sided p-value of <0.2 afteradjusting for age and sex and a hazard ratio (HRR)>1.0. These SNPs areshown in Tables 7-9 (the p-values shown in Tables 7-9 are two-sidedp-values; thus, the one-sided p-values for these SNPs are half of thesetwo-sided p-values). SNPs that predict ischemic stroke after adjustingfor age and sex (two-sided p-value <0.2 and HRR >1.0) in the white ARICparticipants and separately in the black ARIC participants are shown inTable 7 (whites) and Table 8 (blacks). SNPs that predict ischemic strokeafter adjusting for age and sex in both the black and the white ARICpopulations with the same risk alleles are listed in Table 9.

Example Two: SNPs Associated with Stroke in the Cardiovascular HealthStudy (CHS) Overview

74 SNPs, which had been associated with coronary heart disease (CHD)(Shiffman et al., Arterioscler Thromb Vasc Biol. 2008 January;28(1):173-9, incorporated herein by reference in its entirety), wereanalyzed to determine whether these SNPs are associated with incidentischemic stroke. To carry out this analysis, the risk allele wasprespecified for each of the 74 SNPs based on antecedent studies of CHD.Cox proportional hazards models were used that adjusted for traditionalrisk factors to estimate the associations of these SNPs with incidentischemic stroke during 14 years of follow-up in a population-based studyof older adults referred to as the Cardiovascular Health Study (CHS). Asa result of this analysis, the prespecified risk alleles of 7 of the 74SNPs (in HPS1, ITGAE, ABCG2, MYH15, FSTL4, CALM1, and BAT2) wereassociated with increased risk of stroke in white CHS participants(1-sided P<0.05, false discovery rate (FDR)=0.42). In African Americanparticipants, the prespecified risk alleles of 5 SNPs (in KRT4, LY6G5B,EDG1, DMXL2, and ABCG2) were associated with stroke (1-sided P<0.05,FDR=0.55). The Val12Met SNP in ABCG2 was associated with stroke in bothwhite (hazard ratio 1.46, 90% CI 1.05 to 2.03) and African American(hazard ratio 3.59, 90% CI 1.11 to 11.6) participants of CHS.Kaplan-Meier estimates of the 10 year cumulative incidence of strokewere greater among Val allele homozygotes than among Met allele carriersin both white (10% versus 6%) and African American (12% versus 3%)participants of CHS. Thus, the Val12Met SNP in ABCG2 (encoding atransporter of sterols and xenobiotics) was associated with incidentischemic stroke in white and African American participants of CHS.

Materials and Methods

Cardiovascular Health Study

CHS is a prospective population-based study of risk factors forcardiovascular disease, including CHD and stroke, in older adults. Menand women aged 65 years and older were recruited from random samples ofindividuals on Medicare eligibility lists in four U.S. communities(Sacramento County, California; Washington County, Maryland; ForsythCounty, N.C.; and Pittsburgh, Allegheny County, Pennsylvania) and fromage-eligible members of the same households. Potential participants wereexcluded if they were institutionalized, not ambulatory at home, underhospice care, receiving radiation or chemotherapy for cancer, notexpected to remain in the area for at least three years, or unable to beinterviewed. CHS enrolled 5201 participants in 1989-90. An additional687 African American participants entered the cohort in 1992-93.Participants who did not donate DNA or who did not consent to the use oftheir DNA for studies by private companies (n=514) as well asparticipants for whom the amount of DNA samples were insufficient(n=130) were excluded, leaving 5244 participants available for a geneticstudy. The institutional review board at each site approved the studymethods, and all participants gave written informed consent. Details ofCHS design⁷ and recruitment⁸ have been reported.

Participants completed a baseline clinic examination that included amedical history interview, physical examination, and blood draw.⁹Baseline self-reported myocardial infarction (MI) or stroke wasconfirmed by information from the clinic examination or by review ofmedical records or physician questionnaires.¹⁰ Cardiovascular eventsduring follow-up were identified at semi-annual contacts, whichalternated between clinic visits and telephone calls. Suspected eventswere adjudicated according to standard criteria by a physician reviewpanel using information from medical records, brain imaging studies¹¹and, in some cases, interviews with the physician, participant, or aproxy informant.¹² Medicare utilization files were searched to ascertainevents that may have been missed.¹³

At baseline, 722 of the 5244 participants available for a genetic studyhad a history of stroke or MI. Since the risk of incident ischemicstroke might be influenced by whether a patient had had a prior strokeor MI, these 722 participants were excluded from the analysis, leaving4522 (3849 white and 673 African American) participants in this geneticstudy of first incident ischemic stroke. Baseline characteristics ofthese 4522 participants are presented in Table 10. During follow-up, 642participants had an incident non-procedure-related stroke, and 47 ofthese 642 had an MI before their stroke, leaving 595 stroke events. Ofthese 595 stroke events, 72 (12%) were hemorrhagic, 46 (8%) were notclassified for type, and the remaining 477 stroke events were classifiedas ischemic stroke events: the end point for this analysis.

Covariates

Risk estimates for ischemic stroke were adjusted for the followingtraditional risk factors: diabetes mellitus (defined by fasting serumglucose levels of at least 126 mg/dL or the use of either insulin ororal hypoglycemic medications), impaired fasting glucose (defined asfasting glucose levels between 110 and 125 mg/dL¹⁴), hypertension(defined by systolic blood pressure of at least 140 mmHg, diastolicblood pressure of at least 90 mmHg, or a physician's diagnosis ofhypertension plus the use of anti-hypertensive medications¹⁰), currentsmoking, LDL-cholesterol, HDL-cholesterol, and body mass index (BMI).Other covariates included atrial fibrillation, carotid intima-mediathickness (IMT), and genotypes. Atrial fibrillation was identified onthe basis of 12-lead resting ECGs performed at the baseline examination.Tracings were read for atrial fibrillation or flutter at the CHSElectrocardiography Reading Center.¹⁵ Ultrasonography of the common andinternal carotid arteries was also performed at baseline. The IMT wasdefined as the mean of the maximum IMTs of the near and far walls of theleft and right carotid arteries.¹⁶ Genotypes of the CHS participantswere determined by a multiplex method that combines PCR, allele-specificoligonucleotide ligation assays, and hybridization to oligonucleotidescoupled to Luminex®100™ xMAP microspheres (Luminex, Austin, Tex.),followed by detection of the spectrally distinct microsphere on aLuminex 100 instrument (Shiffman et al., Arterioscler Thromb Vasc Biol.2008 January; 28(1):173-9).

Prespecification of Risk Alleles for 74 SNPs Investigated in CHS

For each of the 74 SNPs that were genotyped in CHS, a risk allele wasprespecified based on antecedent data (Shiffman et al., ArteriosclerThromb Vasc Biol. 2008 January; 28(1):173-9). For 14 of the 74 SNPs,genetic associations with CHD have been previously published.¹⁷⁻²¹ Theremaining 60 SNPs were associated with MI in one or more antecedentstudies of MI as described (Shiffman et al., Arterioscler Thromb VascBiol. 2008 January; 28(1):173-9).

Statistics

Since the risk estimate for gene variants can differ between whites andAfrican Americans, the association of SNPs with incident ischemic strokein CHS was investigated in each race separately. Analyses of time toprimary end point were conducted. Follow-up began at CHS enrollment andended on the date of incident stroke of any type, incident MI, death,loss to follow-up, or Jun. 30, 2004, whichever occurred first. Themedian follow-up time was 11.2 years (11.9 years for the 1989-90 cohortand 10.7 years for the African American cohort).

Cox regression models were used to estimate hazard ratios of each SNP.In Model 1, Cox models were adjusted for baseline age (continuous) andsex. In Model 2, Cox models were adjusted for baseline age (continuous),sex, body mass index (continuous), current smoking, diabetes, impairedfasting glucose, hypertension, LDL-cholesterol (continuous), andHDL-cholesterol (continuous). Risk estimates were also further adjustedfor two additional risk factors of ischemic stroke: atrial fibrillationand carotid IMT. The SNP variable in the Cox models was coded as 0 forthe non-risk homozygote, 1 for those who carried 1 copy of the riskallele and 2 for those who carried 2 copies of the risk allele. Thus,the hazard ratios represent the log-additive increase in risk for eachadditional copy of the risk allele a subject carried, compared with thenon-risk homozygotes. Because the hypotheses that the allele associatedwith increased risk of CHD would also be associated with increased riskof ischemic stroke was being testing, a 1-sided P-value was used to testthe significance of the Cox model coefficients. Correspondingly, 90%confidence intervals were estimated for the hazard ratios (for hazardratios greater than one, there is 95% confidence that a true riskestimate is greater than the lower bound of a 90% confidence interval).In white participants, this study had 80% or more power to detectassociations between SNPs and incident ischemic stroke for SNPs thathave relative risks of 1.3 and 1.5 (in an additive model) and riskallele frequencies of 0.13 and 0.05, respectively, assuming an alphalevel of 0.05 and a 1-sided test. In African American participants, thisstudy had 80% or more power to detect associations between SNPs andincident ischemic stroke for SNPs that have relative risks of 1.6 and1.8 (in an additive model) and risk allele frequencies of 0.3 and 0.14,respectively. The cumulative incidence of stroke was estimated by themethod of Kaplan and Meier. Data were analyzed using Stata StatisticalSoftware.²² The influence of multiple testing was evaluated using thefalse discovery rate (FDR)²³ to estimate the expected fraction of falsepositives in a group of SNPs with P values below a given threshold. FDRcalculations were performed with R Statistical Software.²⁴

Results

The baseline characteristics of the 3,849 white and 673 African Americanparticipants of CHS in this genetic study of ischemic stroke arepresented in Table 10. There were 407 first incident ischemic strokeevents in the white participants and 70 in the African Americanparticipants during follow-up (median of 11.2 years). The associationbetween incident ischemic stroke and 74 SNPs that had previously beenfound to be associated with coronary heart disease (CHD) in one or moreantecedent studies (Shiffman et al., Arterioscler Thromb Vasc Biol. 2008January; 28(1):173-9) was investigated. Specifically, for each SNP, itwas determined whether the allele that had been associated withincreased risk of CHD (the risk allele) was also associated withincreased risk of stroke.

In white participants of CHS, it was found that the risk alleles of 7 ofthese 74 SNPs were associated (P<0.05) with increased risk of strokeafter adjusting for traditional risk factors (age, sex, body mass index,smoking, diabetes, impaired fasting glucose, hypertension,LDL-cholesterol, and HDL-cholesterol). These 7 SNPs were in HPS1, ITGAE,ABCG2, MYH15, FSTL4, CALM1, and BAT2. The additive (per allele) hazardratios for stroke ranged from 1.15 to 1.49 (Table 11). In AfricanAmerican participants of CHS, it was found that the risk alleles of 5SNPs (in KRT4, LY6G5B, EDG1, DMXL2, and ABCG2) were associated (P<0.05)with increased risk of stroke after adjusting for traditional riskfactors. The hazard ratios for these 5 SNPs ranged from 1.40 to 3.59(Table 12). The risk estimates for the 11 SNPs that were associated withstroke in either whites or African Americans (Tables 11 and 12) wereessentially unchanged when further adjusted for atrial fibrillation andinternal carotid artery IMT (data not shown).

To account for multiple comparisons, the FDR²³ was estimated for the setof SNPs found to be associated with incident ischemic stroke in CHSparticipants. These FDRs were 0.42 for the 7 SNPs in white participantsand 0.55 for the 5 SNPs in African American participants of CHS.

ABCG2 Val12Met (rs2231137) was associated with incident ischemic strokein both white and African American participants of CHS. The risk ofischemic stroke was higher in Val allele homozygotes than in Met allelecarriers. The adjusted hazard ratio for Val allele homozygotes, comparedwith Met allele carriers, was 1.50 (90% CI 1.06 to 2.12) in whiteparticipants and 3.62 (90% CI 1.11 to 11.9) in African Americanparticipants (Table 13). The 10-year cumulative incidence of ischemicstroke was greater in Val allele homozygotes than in Met allele carriersin both the white (10% versus 6%) and African American (12% versus 3%,FIGS. 1a-1b ) participants of CHS.

Discussion

Among 74 genetic variants tested in CHS, it was found that 7 wereassociated with incident ischemic stroke in white participants and 5were associated with incident ischemic stroke in African Americanparticipants. In particular, an association between the Val allele ofABCG2 Val12Met and increased risk of incident ischemic stroke wasidentified, and this association was consistent in both whites andAfrican Americans.

Three of the 11 gene variants associated with incident ischemic strokein CHS had particularly notable associations with CHD in the antecedentstudies. The first of these 3 gene variants was the Val allele of ABCG2Val12Met (rs2231137). This gene variant had previously been found to beassociated with angiographically defined severe coronary artery disease(CAD) in two case-control studies.²⁰

ABCG2 encodes ATP-binding cassette, subfamily G, member 2, which is aprotein that belongs to a large family of transporters. It is expressedon the cell surface of stem cells in bone marrow and skeletal muscle,²⁵progenitor endothelial cells that are capable of vasculogenesis inadipose tissue,²⁶ and endothelial cells in blood vessels of the heart²⁷and brain²⁸. The ABCG2 protein has been reported recently to transportsterols.^(29, 30) It is interesting to note that the related ATP-bindingcassette proteins ABCA1,³¹ ABCG5, and ABCG8³² are transporters oflipids: variants of these transporters have been shown to cause lipiddisorders such as Tangier disease³¹ and sitosterolemia.³² However, awell known function of the ABCG2 protein is to act as a multi-drugtransporter of anticancer drugs, and the ABCG2 protein is over-expressedin drug-resistant cancer cells.³³ The Met variant of ABCG2 has beenreported to confer lower drug resistance and has an altered pattern oflocalization when compared with the Val variant.³⁴ It is possible thatthe Met variant of the ABCG2 protein may function in the vascularendothelium and have an altered function as a transporter. Homozygotesof the Val allele of ABCG2 (88% of whites and 88% of African Americans)were at higher risk of stroke than carriers of the Met allele in CHS.Since there were only 16 homozygotes of the Met allele, the Methomozygotes were pooled with heterozygotes and used as the referencegroup. The Met allele could also be considered to be a protective allelein that the Met allele carriers had a lower risk of incident ischemicstroke than the Val allele homozygotes.

The second of the 3 gene variants with notable findings in antecedentstudies is the Ala allele of MYH15 Thr1125Ala (rs3900940). In additionto being associated with MI in two antecedent association studies,⁶ itwas associated with increased risk of incident CHD in the whiteparticipants of the Atherosclerosis Risk in Communities Study.²¹ MYH15encodes myosin heavy polypeptide 15 and the Thr1125Ala SNP is located inthe tail domain of the MYH15 protein.³⁵

The third gene variant with notable findings in antecedent studies isthe G allele of rs3814843 in the 3′ untranslated region in CALM1. ThisSNP was associated with angiographically defined severe CAD in twocase-control studies.²⁰ CALM1 encodes calmodulin 1 which binds calciumand functions in diverse signaling pathways, including those involved incell division,³⁶ membrane trafficking,³⁷ and platelet aggregation.³⁸

Thus, a small subset of gene variants previously associated with CHD inantecedent studies were found to also be associated with incidentischemic stroke in CHS. Notably, the Val allele of the Val12Met SNP inABCG2 (which encodes a transporter of sterols and anticancer drugs) wasassociated with increased risk of incident ischemic stroke in both whiteand African American participants of CHS.

REFERENCES (CORRESPONDING TO EXAMPLE TWO)

-   1. Brass L M, Isaacsohn J L, Merikangas K R, Robinette C D. A study    of twins and stroke. Stroke. 1992; 23:221-223-   2. Bak S, Gaist D, Sindrup S H, Skytthe A, Christensen K. Genetic    liability in stroke: a long-term follow-up study of Danish twins.    Stroke. 2002; 33:769-774-   3. Welin L, Svardsudd K, Wilhelmsen L, Larsson B, Tibblin G.    Analysis of risk factors for stroke in a cohort of men born in 1913.    N Engl J Med. 1987; 317:521-526-   4. Jousilahti P, Rastenyte D, Tuomilehto J, Sarti C, Vartiainen E.    Parental history of cardiovascular disease and risk of stroke. A    prospective follow-up of 14371 middle-aged men and women in Finland.    Stroke. 1997; 28:1361-1366-   5. Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, Haase    N, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M,    Meigs J, Moy C, Nichol G, O'Donnell C J, Roger V, Rumsfeld J, Sorlie    P, Steinberger J, Thom T, Wasserthiel-Smoller S, Hong Y. Heart    disease and stroke statistics—2007 update: a report from the    American Heart Association Statistics Committee and Stroke    Statistics Subcommittee. Circulation. 2007; 115:e69-171-   6. Shiffman D, O'Meara E S, Bare L A, Rowland C M, Louie J Z,    Arellano A R, Lumley T, Rice K, Iakoubova O, Luke M M, Young B A,    Malloy M J, Kane J P, Ellis S G, Tracy R P, Devlin J J, Psaty-   B M. Association of gene variants with incident myocardial    infarction in the Cardiovascular Health Study. Arterioscler Thromb    Vasc Biol. 2008; 28:173-179-   7. Fried L P, Borhani N O, Enright P, Furberg C D, Gardin J M,    Kronmal R A, Kuller L H, Manolio T A, Mittelmark M B, Newman A, et    al. The Cardiovascular Health Study: design and rationale. Ann    Epidemiol. 1991; 1:263-276-   8. Tell G S, Fried L P, Hermanson B, Manolio T A, Newman A B,    Borhani N O. Recruitment of adults 65 years and older as    participants in the Cardiovascular Health Study. Ann Epidemiol.    1993; 3:358-366-   9. Cushman M, Cornell E S, Howard P R, Bovill E G, Tracy R P.    Laboratory methods and quality assurance in the Cardiovascular    Health Study. Clin Chem. 1995; 41:264-270-   10. Psaty B M, Kuller L H, Bild D, Burke G L, Kittner S J,    Mittelmark M, Price T R, Rautaharju P M, Robbins J. Methods of    assessing prevalent cardiovascular disease in the Cardiovascular    Health Study. Ann Epidemiol. 1995; 5:270-277-   11. Longstreth W T, Jr., Bernick C, Fitzpatrick A, Cushman M,    Knepper L, Lima J, Furberg C D. Frequency and predictors of stroke    death in 5,888 participants in the Cardiovascular Health Study.    Neurology. 2001; 56:368-375-   12. Price T R, Psaty B, O'Leary D, Burke G, Gardin J. Assessment of    cerebrovascular disease in the Cardiovascular Health Study. Ann    Epidemiol. 1993; 3:504-507-   13. Ives D G, Fitzpatrick A L, Bild D E, Psaty B M, Kuller L H,    Crowley P M, Cruise R G, Theroux S. Surveillance and ascertainment    of cardiovascular events. The Cardiovascular Health Study. Ann    Epidemiol. 1995; 5:278-285-   14. American Diabetes Association. Report of the Expert Committee on    the Diagnosis and Classification of Diabetes Mellitus. Diabetes    Care. 1997; 20:1183-1197-   15. Rautaharju P M, MacInnis P J, Warren J W, Wolf H K, Rykers P M,    Calhoun H P. Methodology of ECG interpretation in the Dalhousie    program; NOVACODE ECG classification procedures for clinical trials    and population health surveys. Methods Inf Med. 1990; 29:362-374-   16. O'Leary D H, Polak J F, Wolfson S K, Jr., Bond M G, Bommer W,    Sheth S, Psaty B M, Sharrett A R, Manolio T A. Use of sonography to    evaluate carotid atherosclerosis in the elderly. The Cardiovascular    Health Study. CHS Collaborative Research Group. Stroke. 1991;    22:1155-1163-   17. Shiffman D, Ellis S G, Rowland C M, Malloy M J, Luke M M,    lakoubova O A, Pullinger C R, Cassano J, Aouizerat B E, Fenwick R G,    Reitz R E, Catanese J J, Leong D U, Zellner C, Sninsky J J, Topol E    J, Devlin J J, Kane J P. Identification of four gene variants    associated with myocardial infarction. Am J Hum Genet. 2005;    77:596-605-   18. Shiffman D, Rowland C M, Louie J Z, Luke M M, Bare L A, Bolonick    J I, Young B A, Catanese J J, Stiggins C F, Pullinger C R, Topol E    J, Malloy M J, Kane J P, Ellis S G, Devlin J J. Gene variants of    VAMP8 and HNRPUL1 are associated with early-onset myocardial    infarction. Arterioscler Thromb Vasc Biol. 2006; 26:1613-1618-   19. lakoubova O A, Tong C H, Chokkalingam A P, Rowland C M,    Kirchgessner T G, Louie J Z, Ploughman L M, Sabatine M S, Campos H,    Catanese J J, Leong D U, Young B A, Lew D, Tsuchihashi Z, Luke M M,    Packard C J, Zerba K E, Shaw P M, Shepherd J, Devlin J J, Sacks F M.    Asp92Asn polymorphism in the myeloid IgA Fc receptor is associated    with myocardial infarction in two disparate populations: CARE and    WOSCOPS. Arterioscler Thromb Vasc Biol. 2006; 26:2763-2768-   20. Luke M M, Kane J P, Liu D M, Rowland C M, Shiffman D, Cassano J,    Catanese J J, Pullinger C R, Leong D U, Arellano A R, Tong C H,    Movsesyan I, Naya-Vigne J, Noordhof C, Feric N T, Malloy M J, Topol    E J, Koschinsky M L, Devlin J J, Ellis S G. A polymorphism in the    protease-like domain of apolipoprotein(a) is associated with severe    coronary artery disease. Arterioscler Thromb Vasc Biol. 2007;    27:2030-2036-   21. Bare L A, Morrison A C, Rowland C M, Shiffman D, Luke M M,    lakoubova O A, Kane J P, Malloy M J, Ellis S G, Pankow J S,    Willerson J T, Devlin J J, Boerwinkle E. Five common gene variants    identify elevated genetic risk for coronary heart disease. Genet    Med. 2007; 9:682-689-   22. StataCorp. Stata Statistical Software: Release 9. 2005-   23. Benjamini Y, Hochberg Y. Controlling the false discovery rate: A    new and powerful approach to multiple testing. Journal of the Royal    Statistical Society. 1995; Serials B:1289-1300-   24. R Development Core Team. R: A language and environment for    statistical computing, reference index version 2.3.0. 2005-   25. Zhou S, Schuetz J D, Bunting K D, Colapietro A M, Sampath J,    Morris J J, Lagutina I, Grosveld G C, Osawa M, Nakauchi H,    Sorrentino B P. The ABC transporter Bcrp1/ABCG2 is expressed in a    wide variety of stem cells and is a molecular determinant of the    side-population phenotype. Nat Med. 2001; 7:1028-1034-   26. Miranville A, Heeschen C, Sengenes C, Curat C A, Busse R,    Bouloumie A. Improvement of postnatal neovascularization by human    adipose tissue-derived stem cells. Circulation. 2004; 110:349-355-   27. Meissner K, Heydrich B, Jedlitschky G, Meyer Zu Schwabedissen H,    Mosyagin I, Dazert P, Eckel L, Vogelgesang S, Warzok R W, Bohm M,    Lehmann C, Wendt M, Cascorbi I, Kroemer H K. The ATP-binding    cassette transporter ABCG2 (BCRP), a marker for side population stem    cells, is expressed in human heart. J Histochem Cytochem. 2006;    54:215-221-   28. Zhang W, Mojsilovic-Petrovic J, Andrade M F, Zhang H, Ball M,    Stanimirovic D B. The expression and functional characterization of    ABCG2 in brain endothelial cells and vessels. Faseb J. 2003;    17:2085-2087-   29. Janvilisri T, Venter H, Shahi S, Reuter G, Balakrishnan L, van    Veen H W. Sterol transport by the human breast cancer resistance    protein (ABCG2) expressed in Lactococcus lactis. J Biol Chem. 2003;    278:20645-20651-   30. Janvilisri T, Shahi S, Venter H, Balakrishnan L, van Veen H W.    Arginine-482 is not essential for transport of antibiotics, primary    bile acids and unconjugated sterols by the human breast cancer    resistance protein (ABCG2). Biochem J. 2005; 385:419-426-   31. Oram J F. Tangier disease and ABCA1. Biochim Biophys Acta. 2000;    1529:321-330-   32. Schmitz G, Langmann T, Heimerl S. Role of ABCG1 and other ABCG    family members in lipid metabolism. J Lipid Res. 2001; 42:1513-1520-   33. Maliepaard M, van Gastelen M A, de Jong L A, Pluim D, van    Waardenburg R C, Ruevekamp-Helmers M C, Floot B G, Schellens J H.    Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected    ovarian tumor cell line. Cancer Res. 1999; 59:4559-4563-   34. Mizuarai S, Aozasa N, Kotani H. Single nucleotide polymorphisms    result in impaired membrane localization and reduced atpase activity    in multidrug transporter ABCG2. Int J Cancer. 2004; 109:238-246-   35. Desjardins P R, Burkman J M, Shrager J B, Allmond L A, Stedman    H H. Evolutionary implications of three novel members of the human    sarcomeric myosin heavy chain gene family. Mol Biol Evol. 2002;    19:375-393-   36. Moisoi N, Erent M, Whyte S, Martin S, Bayley P M.    Calmodulin-containing substructures of the centrosomal matrix    released by microtubule perturbation. J Cell Sci. 2002;    115:2367-2379-   37. Tyteca D, van Ijzendoorn S C, Hoekstra D. Calmodulin modulates    hepatic membrane polarity by protein kinase C-sensitive steps in the    basolateral endocytic pathway. Exp Cell Res. 2005; 310:293-302-   38. Oury C, Sticker E, Cornelissen H, De Vos R, Vermylen J,    Hoylaerts M F. ATP augments von Willebrand factor-dependent    shear-induced platelet aggregation through Ca2+-calmodulin and    myosin light chain kinase activation. J Biol Chem. 2004;    279:26266-26273.

Supplemental Analysis of SNPs in the CHS Study

In a further analysis of 77 SNPs, which include the SNPs analyzed in theCHS study described herein in Example Two along with additional SNPsfound to be associated with CHD risk in a Cholesterol and RecurrentEvent (CARE) trial and a WOSCOPS trial (Shiffman et al., ArteriosclerThromb Vasc Biol. 2008 January; 28(1):173-977), three additional SNPsthat predict ischemic stroke risk were identified by Cox proportionalhazard analysis that had one-sided p-values of <=0.05 in whites afteradjusting for age and sex, and also after adjusting for all traditionalrisk factors including smoking, diabetes, hypertension, HDL-C, LDL-C,and BMI (similar to what was described in Shiffman et al., ArteriosclerThromb Vasc Biol. 2008 January; 28(1):173-9). These three SNPs are shownin Table 14. Also, as shown in Table 14, the hazard ratios wereconsistent in blacks and whites for SNPs rs2243682/hCV1624173 andrs34868416/hCV25951678.

Example Three: SNPs Associated with Noncardioembolic Stroke in theVienna Stroke Registry Overview

For SNPs that had been associated with coronary heart disease (CHD) inprevious studies such as Atherosclerosis Risk in Communities (ARIC)(e.g., Bare, et al. (2007), Genet Med 9(10):682-9 and McPherson, et al.(2007), Science 316(5830):1488-91), carriers of the CHD risk alleles foreach SNP were analyzed for increased risk of noncardioembolic stroke inthe Vienna Stroke Registry (VSR). In a case-control study, 562noncardioembolic stroke cases from VSR⁷ and 815 healthy controls fromthe city of Vienna⁸ were genotyped for each of the SNPs. The allelepreviously associated with CHD risk was pre-specified as the riskallele, and this risk allele was tested for association withnoncardioembolic stroke.

It was determined that carriers of the CHD risk allele of the followingfour SNPs had increased risk of noncardioembolic stroke (the name of thegene or chromosome that contains each SNP is indicated in parentheses):rs3900940 (MYH15), rs20455 (KIF6), rs1010 (VAMP8), and rs10757274(chromosome 9p21) (characteristics of these SNPs are presented in Table16). The odds ratios (OR) for the associations of these SNPs withnoncardioembolic stroke were as follows: 1.20 (90% confidence interval0.95-1.50) for rs10757274 on chromosome 9p21, 1.24 (1.01-1.5) forrs20455 in KIF6, 1.31 (1.07-1.60) for rs3900940 in MYH15, and 1.21(0.99-1.49) for rs1010 in VAMP8.

Subjects and Methods

Study Population

The stroke cases in VSR are consecutive Caucasian patients admitted tostroke units in Vienna within 72 hours of onset of acute ischemic strokebetween October 1998 and June 2001. All patients underwent cranial CT orMRI and were documented according to a standardized protocol includingstroke severity, risk factors, and medical history⁷. Only patients withnoncardioembolic stroke were included as cases in this study. Controlswere unrelated Caucasian participants in a health care program inVienna, 45 years old or older, free of arterial vascular disease, andreported no arterial vascular diseases in first degree relatives⁸.Genotypes were determined as described previously⁹. This study compliedwith the Declaration of Helsinki and was approved by the EthicsCommittee of Medical University Vienna. All subjects gave writteninformed consent.

Statistics

Differences in traditional risk factors between cases and controls wereassessed by the Wilcoxon rank sum test (continuous variables) or by thechi-square test (discrete variables). Odds ratios estimated fromlogistic regression models were adjusted for traditional risk factorsincluding age (at the index stroke event for cases, at enrollment forcontrols), sex, current smoker (versus not), diabetes mellitus (definedby a physician's diagnosis or the use of either insulin or oralhypoglycemic medications), hypertension (defined by systolic bloodpressure >140 mmHg, diastolic blood pressure >90 mmHg, a physician'sdiagnosis of hypertension, or the use of anti-hypertensive medications),dyslipidemia (defined by a total cholesterol ≥240 mg/dL (6.2 mmol/L),LDL-C ≥160 mg/dL (4.1 mmol/L), HDL-C <40 mg/dL (1.0 mmol/L), or the useof lipid lowering medications), and body mass index (BMI). Since thepurpose of this study was to determine if the same alleles found to beassociated with increased risk of CHD in previous studies would beassociated with increased risk of noncardioembolic stroke in VSR,one-sided p values and 90% confidence intervals (because there was 95%confidence that the true risk estimates were greater than the lowerbounds of the 90% confidence intervals) were used. All other p valuesare two-sided. Effect sizes for carriers of the CHD risk alleles,compared with noncarriers, detectable with 90% power were calculatedusing QUANTO¹⁰ assuming a one-sided test and an alpha of 0.05. Toaccount for multiple hypothesis testing, the false discovery rate qvalues were estimated by the method of Benjamini and Hochberg¹¹ usingthe p values for CHD risk allele carrier status from the age and sexadjusted models. The q value of a given SNP represents the expectedproportion of false positives among the set of SNPs with equal or lowerq values.

Structure software was used to estimate both the number ofsubpopulations (due to ancestry) in this study and the degree ofancestry admixture for each individual subject¹² based on genotypes of130 SNPs whose minor allele frequencies ranged from 0.95% to 49.8%. Theprobable degree of admixture was included as a covariate in logisticregression models to adjust risk estimates for potential confounding dueto population structure. Models that assumed one, two, three, or foursubpopulations were tested, and replicate runs of the Structure programwere performed for each model with a burn-in of 20,000 repetitionsfollowed by 10,000 repetitions using the admixture model withindependent allele frequencies and default values for other parameters.

Results

The clinical characteristics of the cases and controls are presented inTable 15. It was determined whether carriers of the alleles of SNPs thathad previously been associated with increased risk of CHD^(2,3) werealso associated with increased risk of noncardioembolic stroke. Thegenotype distribution of these SNPs did not deviate from Hardy Weinbergequilibrium (p>0.17). To account for multiple testing, false discoveryrate q values were estimated for the SNPs. Four of the SNPs were foundto be associated with noncardioembolic stroke with false discovery rateq values at or below 0.15. For these four SNPs, carriers of the CHD riskallele, compared with noncarriers, had increased risk ofnoncardioembolic stroke after adjusting for age and sex: the odds ratioswere 1.20 (90% confidence interval (CI) 0.95-1.50) for the C9p21 SNP,1.24 (CI 1.01-1.52) for the KIF6 SNP, 1.31 (CI 1.07-1.60) for the MYH15SNP, and 1.21 (CI 0.99-1.49) for the VAMP8 SNP (Model 1, Table 17). Onexamination of the homozygous and heterozygous carriers separately, itwas found that for the C9p21 SNP, the homozygous carriers (OR=1.59) inparticular had increased risk (OR of heterozygous carriers=1.05). Theseodds ratios decreased somewhat after adjustment for additional riskfactors (smoking, hypertension, diabetes, dyslipidemia, and BMI) withthe exception of the odds ratio for the VAMP8 SNP which increased (Model2, Table 17). Removal of all cases with a history of myocardialinfarction (n=40) from the analysis did not appreciably change the fullyadjusted odds ratios for the C9p21 homozygotes (1.45, CI 1.05-1.99),MYH15 carriers (1.24, CI 0.99-1.55), and VAMP8 carriers (1.28, CI1.01-1.61). However, removal of cases with a history of myocardialinfarction reduced the odds ratio for KIF6 carriers to 1.15 (CI0.91-1.45).

Population structure was investigated in this study using a Bayesianclustering approach¹² to evaluate models that assumed one, two, three,or four distinct subpopulations. A model assuming two subpopulations wasfound to result in the highest estimated log likelihood. Using the twosubpopulation model, the degree of ancestry admixture was estimated forindividual subjects. The fully adjusted odds ratios of the SNPs shown inTable 17 were not appreciably changed (the largest change was a decreaseof 0.01 in the odds ratio for C9p21 homozygotes) when further adjustedfor the ancestry of the subjects.

Discussion

It was determined that four SNPs were associated with noncardioembolicstroke after adjusting for age and sex when controlling the falsediscovery rate at 0.15. For these four SNPs, carriers of the CHD riskallele (G of rs10757274 on C9p21, Arg of Trp719Arg (rs20455) in KIF6,Ala of Thr1125Ala (rs3900940) in MYH15, and C of rs1010 in VAMP8) alsohad increased risk of noncardioembolic stroke.

MYH15 encodes myosin heavy polypeptide 15, a motor protein of theclass-II sarcomeric myosin heavy chain family. The Thr1125Ala SNP islocated in the coiled-coil rod domain of the MYH15 protein, and theThr1125 residue has been shown to be phosphorylated^(13,14). Since theAla1125 residue could not be phosphorylated, this substitution couldaffect the function of the MYH15 protein.

VAMP8 encodes vesicle associated membrane protein 8 which functions inplatelet degranulation pathways¹⁵. The rs1010 SNP is located in the 3′untranslated region of VAMP8 in a potential microRNA binding site¹⁶.

Thus, this Example demonstrates that carriers of the CHD risk allele ofSNPs rs20455 in KIF6, rs3900940 in MYH15, rs1010 in VAMP8, andrs10757274 on chromosome 9p21 had increased risk of noncardioembolicstroke in VSR.

REFERENCES (CORRESPONDING TO EXAMPLE THREE)

-   1. Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N,    Hailpern S M, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D,    McDermott M, Meigs J, Moy C, Nichol G, O'Donnell C, Roger V, Sorlie    P, Steinberger J, Thom T, Wilson M, Hong Y: Heart disease and stroke    statistics—2008 update: a report from the American Heart Association    Statistics Committee and Stroke Statistics Subcommittee. Circulation    2008; 117:e25-146.-   2. Bare L A, Morrison A C, Rowland C M, Shiffman D, Luke M M,    lakoubova O A, Kane J P, Malloy M J, Ellis S G, Pankow J S,    Willerson J T, Devlin J J, Boerwinkle E: Five common gene variants    identify elevated genetic risk for coronary heart disease. Genet Med    2007; 9:682-689.-   3. McPherson R, Pertsemlidis A, Kavaslar N, Stewart A, Roberts R,    Cox D R, Hinds D A, Pennacchio L A, Tybjaerg-Hansen A, Folsom A R,    Boerwinkle E, Hobbs H H, Cohen J C: A common allele on chromosome 9    associated with coronary heart disease. Science 2007; 316:1488-1491.-   4. Morrison A C, Bare L A, Luke M M, Pankow J S, Mosley T H, Devlin    J J, Willerson J T, Boerwinkle E: Single nucleotide polymorphisms    associated with coronary heart disease predict incident ischemic    stroke in the Atherosclerosis Risk in Communities (ARIC) study.    Cerebrovascular Disease 2008; 26:420-424.-   5. Zee R Y, Ridker P M: Two common gene variants on chromosome 9 and    risk of atherothrombosis. Stroke 2007; 38:e111.-   6. Luke M M, O'Meara E S, Rowland C M, Shiffman D, Bare L A,    Arellano A R, Longstreth W T, Jr., Lumley T, Rice K, Tracy R P,    Devlin J J, Psaty B M: Gene Variants Associated With Ischemic    Stroke. The Cardiovascular Health Study. Stroke 2008.-   7. Lang W: The Vienna Stroke Registry—objectives and methodology.    The Vienna Stroke Study Group. Wien Klin Wochenschr 2001;    113:141-147.-   8. Lalouschek W, Lang W, Mullner M: Current strategies of secondary    prevention after a cerebrovascular event: the Vienna stroke    registry. Stroke 2001; 32:2860-2866.-   9. Shiffman D, Ellis S G, Rowland C M, Malloy M J, Luke M M,    lakoubova O A, Pullinger C R, Cassano J, Aouizerat B E, Fenwick R G,    Reitz R E, Catanese J J, Leong D U, Zellner C, Sninsky J J, Topol E    J, Devlin J J, Kane J P: Identification of four gene variants    associated with myocardial infarction. Am J Hum Genet 2005;    77:596-605.-   10. QUANTO: Release 1.1 A computer program for power and sample size    calculations for genetic epidemiology studies. Gauderman WJMJ. 2006.-   11. Benjamini Y, Hochberg Y: Controlling the false discovery rate: A    new and powerful approach to multiple testing. Journal of the Royal    Statistical Society 1995; Serials B:1289-1300.-   12. Pritchard J K, Stephens M, Donnelly P: Inference of population    structure using multilocus genotype data. Genetics 2000;    155:945-959.-   13. Gnad F, Ren S, Cox J, Olsen J V, Macek B, Oroshi M, Mann M:    PHOSIDA (phosphorylation site database): management, structural and    evolutionary investigation, and prediction of phosphosites. Genome    Biol 2007; 8:R250.-   14. Olsen J V, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P,    Mann M: Global, in vivo, and site-specific phosphorylation dynamics    in signaling networks. Cell 2006; 127:635-648.-   15. Polgar J, Chung S H, Reed G L: Vesicle-associated membrane    protein 3 (VAMP-3) and VAMP-8 are present in human platelets and are    required for granule secretion. Blood 2002; 100:1081-1083.-   16. Shiffman D, Rowland C M, Louie J Z, Luke M M, Bare L A, Bolonick    J I, Young B A, Catanese J J, Stiggins C F, Pullinger C R, Topol E    J, Malloy M J, Kane J P, Ellis S G, Devlin J J: Gene variants of    VAMP8 and HNRPUL1 are associated with early-onset myocardial    infarction. Arterioscler Thromb Vasc Biol 2006; 26:1613-1618.-   17. Helgadottir et al.: The same sequence variant on 9p21 associates    with myocardial infarction, abdominal aortic aneurysm and    intracranial aneurysm. Nat Genet 2008; 40:217-224.

Supplemental Analysis of SNPs in the Vienna Stroke Registry

In a further analysis, the genotype of 19 SNPs (which were previouslyfound to be associated with incident CHD in white or black participantsof the ARIC study) were determined in the cases and controls of theVienna Stroke Registry (“VSR”, approximately 764 ischemic stroke caseswhich included 562 atherothrombotic stroke cases, and 815 controls whowere 45 or older from the same region).

As shown in Table 18, the risk alleles (which were associated with CHDin ARIC) for certain of these 19 SNPs were found to be associated(2-sided p-value of <0.2) with ischemic stroke (labeled “ischemic” inthe “outcome” column of Table 18), atherothrombotic stroke (labeled“athero” in the “outcome” column of Table 18), and/or early-onset stroke(labeled “early-onset” in the “outcome” column of Table 18) in VSRbefore and/or after adjustment for traditional risk factors such as age,sex, body mass index, smoking, diabetes, impaired fasting glucose,hypertension, LDL-cholesterol, and HDL-cholesterol (results afteradjustment are labeled “yes” and results before adjustment are labeled“no” in the “adjust?” column of Table 18) (the p-values shown in Table18 are two-sided p-values; thus, the one-sided p-values for these SNPsare half of these two-sided p-values).

Early-onset stroke is ischemic stroke that occurs early in life. As usedherein, early-onset stroke is defined as those stroke events thathappened before the median stroke age of the ischemic cases. Thecontrols for these early-onset cases are those controls who were at agesabove the median age of all controls in the study (i.e., young casesversus old controls was the study design).

Example Four: SNPs Associated with Stroke in the UCSF/CCF Study

The allele frequencies of 25,878 putative functional SNPs weredetermined in atherothrombotic stroke cases and healthy controls of theVienna Stroke Registry (“VSR”, about 562 cases and 815 controls, StudyID V0031), and the allele frequencies of about 3,300 of these 25,878SNPs were found to be associated with atherothrombotic(noncardioembolic) stroke (2-sided p value of less than or equal to0.05). These 3,300 SNPs were then further tested in a stroke study ofcases with a history of stroke and controls with no history of stroke ormyocardial infarction from the UCSF and the CCF sample sets (Study IDGS41). The allele frequencies of 292 of these 3,300 SNPs were againassociated with stroke risk (1-sided p<0.05) in the UCSF/CCF strokestudy (approximately 570 cases and 1604 controls), and the risk alleleswere the same in VSR and in UCSF/CCF studies. These stroke associationswere then confirmed by individually genotyping the 292 SNPs in VSRsubjects, and 101 of these SNPs were again found to be associated withstroke risk (p<0.05 in allelic, additive, dominant, or recessive mode).These 101 SNPs were then genotyped in the UCSF/CCF stroke study and itwas determined that 61 of these SNPs were still associated with strokein the UCSF/CCF study (1-sided p<0.05 or 2-sided p<0.1) and have thesame risk allele as in the VSR study.

These 61 SNPs and the stroke association data in both the UCSF/CCF andthe VSR studies are provided in Table 19. These SNPs were furtheranalyzed in additional sample sets, as discussed below in Examples Five,Six, and Seven.

Example Five: SNPs Associated with Stroke in the German West Study

The identification of 61 SNPs that are associated with stroke in both oftwo case-control studies (Vienna Stroke Registry and the UCSF/CCF StrokeStudy) is described in Example Four above. Here, Example Five describesthe analysis of these 61 SNPs, plus 17 additional SNPs, in the GermanWest Study (which may be interchangeably referred to herein as the“Muenster” Stroke Study).

The German West Study, which is a stroke case-control study, included1,300 ischemic stroke cases and 1,000 healthy controls. The ischemicstroke cases were further classified by TOAST criteria into severalstroke subtypes, allowing analyses of the association of genotypes ofthe tested SNPs with the following endpoints: 1) ischemic stroke(outcome: “ischemic_stk” in Tables 20-21), 2) noncardioembolic stroke(outcome: “nonce_stk” in Tables 20-21; ischemic stroke that were notcardioembolic in origin), 3) cardioembolic stroke (outcome: “CE_stk” inTables 20-21), 4) atherothrombotic stroke (outcome: “athero_stk” inTables 20-21), 5) Lacunar stroke (outcome: “lacunar_stk” in Tables20-21), 6) no heart disease stroke (outcome: “nohd_stk” in Tables 20-21;ischemic stroke cases excluding those with a history of heart disease),7) recurrent stroke (outcome: “recurrent_stk” in Tables 20-21; strokecases that also had a prior history of stroke), and 8) early onsetstroke (outcome: “EO_stk” in Tables 20-21; cases that are younger thanthe median age of all cases, and controls that were older than themedian age of all controls).

Potential population stratification was also adjusted for (in additionto traditional risk factors) in assessing the risk estimates of theSNPs. The risk allele of each of the SNPs tested in this study waspre-specified to be the same as in antecedent studies, and a 2-sidedp-value of less than 0.1 (equivalent to 1-sided p-values less than 0.05)or a 2-sided p-value less than 0.2 (equivalent to 1-sided p-values lessthan 0.1) were used as cutoffs for statistical significance.

SNPs that showed significant association with stroke risk in the GermanWest Study are provided in Tables 20-21. Table 20 provides SNPsassociated with stroke that have the same risk allele and 2-sidedp-values that are less than 0.1 (equivalent to 1-sided p-values that areless than 0.05), and Table 21 provides SNPs associated with stroke thathave the same risk allele and 2-sided p-values that are between 0.1 and0.2 (equivalent to 1-sided p-values that are between 0.05 and 0.1).

Supplemental Analysis of SNPs in the German West Study

Overview and Results

Also in the German West Study, SNPs were identified that are associatedwith noncardioembolic stroke in three large study populations (theGerman West Study, as well as in the Vienna and UCSF/CCF Studiesdescribed above). A case-control study design was used: the ViennaStudy, the UCSF/CCF Study, and the German West Study (728noncardioembolic stroke cases, 1,041 controls). It was determinedwhether the alleles of those SNPs that were associated with increasedrisk in both the Vienna and UCSF/CCF studies were also associated withincreased risk in the German West Study (thus, 1-sided tests ofsignificance were used). Logistic regression analysis adjusting for age,sex, hypertension, and diabetes was performed.

Four SNPs were determined to be associated with noncardioembolic stroke(p<0.05) in the German West Study (before correcting for multipletesting—46 SNPs and 3 genetic models), as well as also being associatedwith noncardioembolic stroke in the UCSF/CCF and Vienna studiesdescribed above. These four SNPs (and the genes which they are in ornear) are as follows: rs544115 in NEU3, rs1264352 near DDR1, rs10948059in GNMT, and rs362277 in HD. An increased risk for noncardioembolicstroke was observed for carriers of the following genotypes, comparedwith noncarriers, for each of these four SNPs (with carrier frequency incontrols, odds ratio, and 90% confidence interval indicated): CT or CCcarriers of rs544115 (96.0% of controls, OR 2.39, CI 1.31-4.36), CG orCC carriers of rs1264352 (23.9% of controls, OR 1.38, CI 1.08-1.76), CTor CC carriers of rs10948059 (77% of controls, OR 1.38, CI 1.06-1.79),and CC carriers of rs362277 (80.0% of controls, OR 1.39, CI 1.05-1.84).After correcting for multiple testing, this set of 4 SNPs had a falsediscovery rate (FDR) of 0.67.

Subjects and Methods

Study Subjects

Subjects in all three studies (the German West Study, as well as theVienna and UCSF/CCF Studies) were unrelated men and women of Europeandecent and have given written informed consent. In the Vienna Study, thenoncardioembolic stroke cases (defined as ischemic stroke cases that arenot of cardioembolic origin, and included large vessel and small vesselstroke) were drawn from the Vienna Stroke Registry (VSR). Stroke casesin VSR were consecutive Caucasian patients admitted to stroke units inVienna within 72 hours of onset of acute ischemic stroke between October1998 and June 2001. All patients underwent cranial CT or MRI and weredocumented according to a standardized protocol including strokeseverity, risk factors, and medical history. Controls were unrelatedCaucasian participants in a health care program in Vienna, 45 years oldor older, free of arterial vascular disease, and reported no arterialvascular diseases in first degree relatives. This study complied withthe Declaration of Helsinki and was approved by the Ethics Committee ofMedical University Vienna.

The UCSF/CCF study included 416 cases and 977 controls drawn fromGenomic Resource at University of California San Francisco (UCSF) aswell as 154 cases and 627 controls drawn from the Genebank of ClevelandClinic Foundation (CCF). Cases in the UCSF/CCF study did not have strokesubtype information. To enrich for noncardioembolic stroke cases,patients with a history of stroke were excluded who also had a historyof heart rhythm or heart valve diseases that could have lead tocardioembolic stroke. Cases from UCSF had a history of stroke and nohistory of abnormal heart rhythm, heart valve disease or surgery.Controls from UCSF did not have a history of stroke, atherectomy, or CHD(including coronary stenosis, myocardial infarction, or coronaryrevascularization procedures). Cases and controls from CCF were patientswho have had coronary angiography. Cases had a history of stroke and nohistory of atrial fibrillation, heart valve disease, or surgery.Controls did not have a history of stroke or CHD (including myocardialinfarction, coronary stenosis greater than 50%, peripheral vasculardisease, or revascularization procedures).

The German West Study included 728 noncardioembolic cases (ischemicstrokes that were not of cardioembolic origin) from Westphalia StrokeRegistry and 1,041 controls from the same region of Germany recruited bythe Dortmund Health Study for the noncardioembolic stroke analysis. Forthe cardioembolic stroke analysis, 462 cardioembolic stroke cases(ischemic strokes of cardioembolic origin), also enrolled in theWestphalia Stroke Registry, were compared with the same 1401 controlsfrom the Dortmund Health Study.

Statistics

Differences in traditional risk factors between cases and controls wereassessed by the Wilcoxon rank sum test (continuous variables) or by thechi-square test (discrete variables). Odds ratios for the Vienna Studyor the UCSF/CCF Study were not adjusted, and odds ratios for the GermanWest Study were estimated from logistic regression models and adjustedfor traditional risk factors including age (at the index stroke eventfor cases, at enrollment for controls), sex, diabetes mellitus (definedby a physician's diagnosis or the use of either insulin or oralhypoglycemic medications), hypertension (defined by systolic bloodpressure >140 mmHg, diastolic blood pressure >90 mmHg, a physician'sdiagnosis of hypertension, or the use of anti-hypertensive medications).To account for multiple hypothesis testing, the false discovery rate(FDR) q values were estimated by the method of Benjamini and Hochberg(Journal of the Royal Statistical Society 1995; Serials B:1289-1300)using the p-values for risk genotype carrier status from the modeladjusted for age, sex, hypertension, and diabetes.

Example Six: SNPs Associated with Stroke or Statin Response in CARE orPROSPER Studies

The identification of 61 SNPs that are associated with stroke in both oftwo case-control studies (Vienna Stroke Registry and the UCSF/CCF StrokeStudy) is described in Example Four above. Example Five above describesthe analysis of these 61 SNPs plus 17 additional SNPs in the German WestStudy. Here, Example Six describes the analysis of SNPs for associationwith stroke risk and stroke statin response (SSR) in two pravastatintrials: CARE (“Cholesterol and Recurrent Events” study, which iscomprised of individuals who have previously had an MI) and PROSPER(“Prospective Study of Pravastatin in the Elderly at Risk” study, whichis comprised of elderly individuals with or without a history ofcardiovascular disease (CVD)).

In CARE, SNPs were analyzed for association with stroke risk or SSR.SNPs that were significantly associated with stroke risk or SSR in CARE(which were also associated with stroke risk in the German West Studydescribed above in Example Five) are provided in Table 22 (stroke risk)and Table 23 (SSR). Additional SNPs that were significantly associatedwith stroke risk or SSR in CARE are provided in Table 24 (stroke risk)and Table 25 (SSR). Further SNPs that were significantly associated withstroke risk or SSR in CARE are provided in Table 26 (stroke risk) andTable 27 (SSR).

Table 26 shows that, for example, individuals in CARE who were G/Ghomozygotes at the CALM1 SNP (rs3814843/hCV11474611) had an increasedrisk for stroke (HR=7.54 with a 2-sided p-value of 0.0441 for genotypicmode and adjusted for statin use; HR=7.43 with a 2-sided p-value of0.0455 for recessive mode and adjusted for statin use; HR=6.64 with a2-sided p-value of 0.0606 for genotypic mode and unadjusted; and HR=6.67with a 2-sided p-value of 0.0599 for recessive mode and unadjusted).

Results of the analysis of the MYH15 SNP (rs3900940/hcv7425232) forassociation with stroke risk in CARE are provided in Table 28. Table 28shows that, for example, individuals in CARE who were C/C homozygotes atthe MYH15 SNP (rs3900940/hcv7425232) had an increased risk for stroke(HR=1.403 with a 2-sided p-value of 0.153 when adjusted for statin use;HR=1.51 with a 2-sided p-value of 0.086 when adjusted for traditionalrisk factors, BMI, and statin use; and HR=1.49 with a 2-sided p-value of0.094 when adjusted for CHD, traditional risk factors, BMI, and statinuse). All the p-values (including P_(int) values) provided in Tables22-28 are two-sided p-values.

In PROSPER, SNPs were analyzed for association with stroke risk or SSR,in the whole study cohort (strata: “ALL”), or in the subgroup with ahistory of CVD (strata: “hist”) or without a CVD history (strata: “nohist”). SNPs were considered significantly associated with stroke riskif they met the p-value cutoffs and had the same risk allele as inantecedent studies (e.g., as described herein in Examples Four, Five,and Six), and these SNPs that are significantly associated with strokerisk are provided in Tables 29-30. Specifically, Table 29 lists SNPsassociated with stroke risk that have P_all<0.2 (which is the p-valuebased on the entire study cohort), and Table 30 lists SNPs associatedwith stroke risk that have P_placebo<0.2 (which is the p-value based onjust the placebo arm of the trial). For SSR, the results of the analysesof pravastatin-treated versus placebo-treated individuals are providedin Table 31 (which lists SNPs having P_(int)<0.1) and Table 32 (whichlists SNPs having P_(int)<0.2). All the p-values (including P_(int)values) provided in Tables 29-32 are two-sided p-values (two-sidedp-value cutoffs of 0.1 and 0.2 are equivalent to one-sided p-valuecutoffs of 0.05 and 0.1, respectively).

Table 30 shows that, for example, individuals in PROSPER who were A/Gheterozygotes at the chromosome 9p21 SNP (rs1075727/hCV26505812) had anincreased risk for stroke (HR=1.464 with a 2-sided p-value of 0.035based on the placebo group; see the first row for rs10757274/hCV26505812in Table 30).

Table 30 also shows that, for example, individuals in PROSPER who wereT/T homozygotes at the chromosome 4q25 SNP (rs2200733/hCV16158671) hadan increased risk for stroke (HR=3.711 with a 2-sided p-value of 0.025based on the placebo group).

Also in the CARE and PROSPER trials, the chromosome 9p21 SNP rs10757274(hCV26505812) was analyzed further for association with SSR, includingunadjusted and adjusted analysis. Adjusted analysis in CARE (Table 37)was adjusted for age, gender, smoking status, hypertension, diabetes,body mass index (BMI), and LDL and HDL levels, and adjusted analysis inPROSPER (Table 38) was adjusted for country, gender, age, LDL, HDL,smoking status (current vs. past or never), history of hypertension, anddiabetes. Table 37 provides results in CARE, and Table 38 providesresults in PROSPER (whether each analysis is unadjusted or adjusted isindicated in the “adjust” column in Table 37, or by “unadj” and “adj”column labels in Tables 38). All the p-values (including P_(int) values)provided in Tables 37-38 are two-sided p-values.

In CARE, among the three genotypes of SNP rs1075727 (homozygous carriersof each of the two alternative alleles plus heterozygous carriers), theheterozygous carriers of SNP rs10757274 (49% genotype frequency) had thegreatest reduction in the number of stroke events (HR=0.61) uponpravastatin treatment after adjusting for traditional risk factors(2-sided p-value=0.034, and the genotype by treatment interaction had a2-sided p-interaction value (“pval_intx” or P_(int))=0.44; see the13^(th) row under the column headings in Table 37). In PROSPER,heterozygous carriers of the G allele (risk allele) at SNP rs1075727 inthe placebo arm had an increased stroke risk (for example, see the firstrow for rs10757274/hCV26505812 in Table 30), as indicated above.Furthermore, in PROSPER, after stratifying by rs10757274 genotype,heterozygous carriers of this SNP (51% of the population) also had thegreatest reduction in the number of stroke events (unadjusted HR=0.777)in the pravastatin-treated versus the placebo-treated arms of the trial(2 sided p-value=0.066; see the 3rd row under the column headings inTable 38), whether unadjusted or adjusted for traditional risk factors.

Example Seven: SNPs Associated with Stroke in the Cardiovascular HealthStudy (CHS)

The identification of 61 SNPs that are associated with stroke in both oftwo case-control studies (Vienna Stroke Registry and the UCSF/CCF StrokeStudy) is described in Example Four above. Example Five above describesthe analysis of these 61 SNPs plus 17 additional SNPs in the German WestStudy. Here, Example Seven describes the analysis of SNPs previouslyfound to be associated with stroke (e.g., in Examples Four, Five, and/orSix above) for association with incident stroke events in theCardiovascular Health Study (CHS), which is a population-based study ofelderly white or black participants in the United States. Associationwas analyzed for three related stroke end points: stroke (all subtypes)(endpoint: “stroke” in Tables 33-36), ischemic stroke (excludeshemorrhagic stroke) (endpoint: “ischem” in Tables 33-36), andatherothrombotic stroke (excludes hemorrhagic stroke and cardioembolicstroke) (endpoint: “athero” in Tables 33-36).

The results in the CHS Study are provided in Tables 33-36. Specifically,SNPs that are associated with stroke risk in white or black individualswith 2-sided p-values less than 0.1 (equivalent to 1-sided p-values lessthan 0.05) are provided in Table 33 (white individuals) and Table 34(black individuals), and SNPs that are associated with stroke in whiteor black individuals with 2-sided p-values between 0.1 and 0.2(equivalent to 1-sided p-values between 0.05 and 0.1) are provided inTable 35 (white individuals) and Table 36 (black individuals).

Example Eight: Additional LD SNPs Associated with Stroke

Another investigation was conducted to identify SNPs in linkagedisequilibrium (LD) with certain “interrogated SNPs” which have beenfound to be associated with stroke, as described herein and shown in thetables. The interrogated SNPs are shown in column 1 (which indicates thehCV identification numbers of each interrogated SNP) and column 2 (whichindicates the public rs identification numbers of each interrogated SNP)of Table 4. The methodology is described earlier in the instantapplication. To summarize briefly, the power threshold (T) was set at anappropriate level, such as 51%, for detecting disease association usingLD markers. This power threshold is based on equation (31) above, whichincorporates allele frequency data from previous disease associationstudies, the predicted error rate for not detecting trulydisease-associated markers, and a significance level of 0.05. Using thispower calculation and the sample size, a threshold level of LD, or r²value, was derived for each interrogated SNP (r_(T) ², equations (32)and (33) above). The threshold value r_(T) ² is the minimum value oflinkage disequilibrium between the interrogated SNP and its LD SNPspossible such that the non-interrogated SNP still retains a powergreater or equal to T for detecting disease association.

Based on the above methodology, LD SNPs were found for the interrogatedSNPs. Several exemplary LD SNPs for the interrogated SNPs are listed inTable 4; each LD SNP is associated with its respective interrogated SNP.Also shown are the public SNP IDs (rs numbers) for the interrogated andLD SNPs, when available, and the threshold r² value and the power usedto determine this, and the r² value of linkage disequilibrium betweenthe interrogated SNP and its corresponding LD SNP. As an example inTable 4, the interrogated, stroke-associated SNP rs11580249(hCV11548152) was calculated to be in LD with rs12137135 (hCV30715059)at an r² value of 0.4781, based on a 51% power calculation, thusestablishing the latter SNP as a marker associated with stroke as well.

In general, the threshold r_(T) ² value can be set such that one ofordinary skill in the art would consider that any two SNPs having an r²value greater than or equal to the threshold r² value would be insufficient LD with each other such that either SNP is useful for thesame utilities, such as determining an individual's risk for stroke. Forexample, in various embodiments, the threshold r_(T) ² value used toclassify SNPs as being in sufficient LD with an interrogated SNP (suchthat these LD SNPs can be used for the same utilities as theinterrogated SNP, for example, such as determining stroke risk) can beset at, for example, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 0.96, 0.97, 0.98,0.99, 1, etc. (or any other r² value in-between these values). Thresholdr_(T) ² values may be utilized with or without considering power orother calculations.

All publications and patents cited in this specification are hereinincorporated by reference in their entirety. Various modifications andvariations of the described compositions, methods and systems of theinvention will be apparent to those skilled in the art without departingfrom the scope and spirit of the invention. Although the invention hasbeen described in connection with specific preferred embodiments andcertain working examples, it should be understood that the invention asclaimed should not be unduly limited to such specific embodiments.Indeed, various modifications of the above-described modes for carryingout the invention that are obvious to those skilled in the field ofmolecular biology, genetics and related fields are intended to be withinthe scope of the following claims.

TABLE 3 CD000022ORD Marker Alleles Primer 1 (Allele-specific Primer)Primer 2 (Allele-specific Primer) Common Primer hCV1022614 C/TCTGCAGCCTCTCCTACG (SEQ ID NO: 1567) CCTGCAGCCTCTCCTACA (SEQ ID NO: 1568)GATTCCCCATCGGTCATAA (SEQ ID NO: 1569) hCV1053082 C/TTTGCAGAGAAGCGTTCC (SEQ ID NO: 1570)CTTTGCAGAGAAGCGTTCT (SEQ ID NO: 1571)CTGAGCTTTGTGAAGAGAAACTGA (SEQ ID NO: 1572) hCV1116757 C/TGACAAACTGAGGGACAACG (SEQ ID NO: 1573)GACAAACTGAGGGACAACA (SEQ ID NO: 1574)CCTCTGACAGACGCTTCTTGA (SEQ ID NO: 1575) hCV1116793 C/TGGAAGGTCATCCTGGG (SEQ ID NO: 1576) GGAAGGTCATCCTGGA (SEQ ID NO: 1577)CGAAGAGTTTCTGTGTGGTACAG (SEQ ID NO: 1578) hCV11354788 C/TTGAGACGGGTGGTAACC (SEQ ID NO: 1579) TTGAGACGGGTGGTAACT (SEQ ID NO: 1580)CAGCTTTGAAGGGCATCCATATGA (SEQ ID NO: 1581) hCV11425801 C/TTCCCACACCACCTGC (SEQ ID NO: 1582) CTCCCACACCACCTGT (SEQ ID NO: 1583)GCCACCACAATGTCTCTCAATAC (SEQ ID NO: 1584) hCV11425842 C/TCCGCTCCGCACTTAAAG (SEQ ID NO: 1585) CCGCTCCGCACTTAAAA (SEQ ID NO: 1586)CCTGCAGCTGGACAGACTC (SEQ ID NO: 1587) hCV11450563 G/TTAAAGAATGCATAAATTAGTGTGG (SEQ IDTTAAAGAATGCATAAATTAGTGTGT (SEQ ID NO: 1589)GATCCTAATTGGATTTGAAGACTTA (SEQ ID NO: 1590) NO: 1588) hCV11474611 G/TATCGCCCATGTGCTG (SEQ ID NO: 1591) CATCGCCCATGTGCTT (SEQ ID NO: 1592)TCAAACCAGGAACCCTATCT (SEQ ID NO: 1593) hCV11548152 G/TCTGTAAACGCTGGTCTGG (SEQ ID NO: 1594)ACTGTAAACGCTGGTCTGT (SEQ ID NO: 1595)CCTTGTCCCTGATTGCTTCTTCA (SEQ ID NO: 1596) hCV11738775 C/TCCCCGCTTCAACACG (SEQ ID NO: 1597) TCCCCGCTTCAACACA (SEQ ID NO: 1598)AACTTCATTCGGCACTTGCTACAA (SEQ ID NO: 1599) hCV11758801 C/GAGTACCTCTTGGTCTCTCTCC (SEQ ID NO: 1600)AGTACCTCTTGGTCTCTCTCG (SEQ ID NO: 1601)GCATGTTGTGTTTCTGATTGTAC (SEQ ID NO: 1602) hCV11861255 A/GAAAGGGCCGAGCTGATA (SEQ ID NO: 1603) AGGGCCGAGCTGATG (SEQ ID NO: 1604)GGGAGGTTTGGAGAGAGAGTAT (SEQ ID NO: 1605) hCV12071939 G/TGACCGTGGTCCCTTG (SEQ ID NO: 1606) TGACCGTGGTCCCTTT (SEQ ID NO: 1607)CGCCCGGAGACAGAA (SEQ ID NO: 1608) hCV1209800 G/TTAGCAACTGCTATCAATGACAG (SEQ ID NO: 1609)TAGCAACTGCTATCAATGACAT (SEQ ID NO: 1610)AGTGAAGGAGTTAACTGAGTGTGTA (SEQ ID NO: 1611) hCV1262973 A/GTGGGTCCCAAGCTCAT (SEQ ID NO: 1612) TGGGTCCCAAGCTCAC (SEQ ID NO: 1613)GGCTCGCCGACACTG (SEQ ID NO: 1614) hCV1305848 A/GACATTTATACCATTTCCCGAGT (SEQ ID NO: 1615)ACATTTATACCATTTCCCGAGC (SEQ ID NO: 1616)GCCTAACAACAGTACCTACTCCATAGG (SEQ ID NO: 1617) hCV1348610 A/GCATTTGTCCTAAAAGTACCTCTCT (SEQ IDCATTTGTCCTAAAAGTACCTCTCC (SEQ ID NO: 1619)CAAGGCTAAGCATGCTGAACACA (SEQ ID NO: 1620) NO: 1618) hCV1408483 C/TTGCTAAGGCCTGTGAAC (SEQ ID NO: 1621) TTGCTAAGGCCTGTGAAT (SEQ ID NO: 1622)TCTGTTTTCGCTGGAGTCTT (SEQ ID NO: 1623) hCV1452085 A/CACACCCTGACACCTCTTTTACT (SEQ ID NO: 1624)ACCCTGACACCTCTTTTACG (SEQ ID NO: 1625)CGTTCCAGTCCATATTCACAT (SEQ ID NO: 1626) hCV1463226 C/TATTTCCTCCCTCACATGATAC (SEQ ID NO: 1627)ATTTCCTCCCTCACATGATAT (SEQ ID NO: 1628)TCAAAGAATGAAGAGTGAAGACA (SEQ ID NO: 1629) hCV15752716 C/TACGCTGCTGTTCCG (SEQ ID NO: 1630) ACGCTGCTGTTCCA (SEQ ID NO: 1631)CAGACAGACAACAATTCAGAAGAA (SEQ ID NO: 1632) hCV15770510 G/TTGAAGACTGATTGTTGTACTTGC (SEQ IDCTGAAGACTGATTGTTGTACTTGA (SEQ ID NO: 1634)TGGTGGAGAGGGTTGTAGAA (SEQ ID NO: 1635) NO: 1633) hCV15851766 A/GGAGTTTTCGCCATCCACT (SEQ ID NO: 1636) GTTTTCGCCATCCACC (SEQ ID NO: 1637)GAATCTGCTTCATTTGAATCTCT (SEQ ID NO: 1638) hCV15854171 C/TTTGGTGTTTCCTTGTGACAC (SEQ ID NO: 1639)TTGGTGTTTCCTTGTGACAT (SEQ ID NO: 1640)CCTAGTGTTTGCAATCTCATTTATC (SEQ ID NO: 1641) hCV15857769 C/TCACTCCTAAGTGAGCAGC (SEQ ID NO: 1642)ATCACTCCTAAGTGAGCAGT (SEQ ID NO: 1643)CTGCTTCAGTGTTATCTCAGTCTT (SEQ ID NO: 1644) hCV15879601 C/TCCACCAGGATGTAACAGTCC (SEQ ID NO: 1645)CCCACCAGGATGTAACAGTCT (SEQ ID NO: 1646)TGTGGATGCAGCAGTGAC (SEQ ID NO: 1647) hCV16093418 A/GCAAGAAGTTCACAGCTGAAGA (SEQ ID NO: 1648)AAGAAGTTCACAGCTGAAGG (SEQ ID NO: 1649)CCTGCTGGAGAGACAGAGTG (SEQ ID NO: 1650) hCV16134786 A/GGGCAGGGGTGAGATTGA (SEQ ID NO: 1651) GGCAGGGGTGAGATTGG (SEQ ID NO: 1652)GTCGTGAGGTCAGATGCTATGAG (SEQ ID NO: 1653) hCV16158671 C/TCTTAAATATTACCTGTTCTAATTTTCTCTG (SEQ IDCCTTAAATATTACCTGTTCTAATTTTCTCTA (SEQ IDGAAATGCTGTGGGAACATAAACTAACTAGG (SEQ ID NO: 1654) NO: 1655) NO: 1656)hCV16164743 NC GAGCAATAGTAAGTATACACAATGAAATAA (SEQ IDGAGCAATAGTAAGTATACACAATGAAATAC (SEQ IDGATCACGGGCCTCTAGATTGATTACA (SEQ ID NO: 1659) NO: 1657) NO: 1658)hCV1619596 A/G GAGGAGCCCGTTGCA (SEQ ID NO: 1660)AGGAGCCCGTTGCG (SEQ ID NO: 1661) TCACCATGCACAAGGACA (SEQ ID NO: 1662)hCV1624173 A/G TGGACAACAGCACCTTAT (SEQ ID NO: 1663)TGGACAACAGCACCTTAC (SEQ ID NO: 1664)TTCCAGAGGTTCCTTCAATC (SEQ ID NO: 1665) hCV16336 C/TCCCCTCAAGCACTCTGAC (SEQ ID NO: 1666)CCCCTCAAGCACTCTGAT (SEQ ID NO: 1667)TCTGCCCCTCGTCTTTCTCT (SEQ ID NO: 1668) hCV1690777 A/GGGCTTTACAGAAGGAAATGCT (SEQ ID NO: 1669)GCTTTACAGAAGGAAATGCC (SEQ ID NO: 1670)GCATGCGCTGAATTTTATATAG (SEQ ID NO: 1671) hCV1723718 A/GCAGCCGTTTCTTCATATAATCCA (SEQ ID AGCCGTTTCTTCATATAATCCG (SEQ ID NO: 1673)CTTGCTAATTCATTCTGTGACCTCAAT (SEQ ID NO: 1674) NO: 1672) hCV1746715 A/GGCGCCTTTCTGTGTAGTT (SEQ ID NO: 1675)GCGCCTTTCTGTGTAGTC (SEQ ID NO: 1676)CACAACAGTTGTTAAGTTGTTAGCAAACC (SEQ ID NO: 1677) hCV1754669 A/GTTCAGGCCATCTTGCAAAT (SEQ ID NO: 1678)TCAGGCCATCTTGCAAAC (SEQ ID NO: 1679)CTCATGGCCCGATGATTTTCAGTTA (SEQ ID NO: 1680) hCV1846459 C/TCAGGCTCGTCTTGAACTC (SEQ ID NO: 1681)CAGGCTCGTCTTGAACTT (SEQ ID NO: 1682)CAAGAGTGGGAACTGCAGGTTT (SEQ ID NO: 1683) hCV1958451 G/TGTGGGAGTCTTATGTTTGTAGATG (SEQ IDGTGGGAGTCTTATGTTTGTAGATT (SEQ ID NO: 1685)GCTTGACAATGCGCAGTTGT (SEQ ID NO: 1686) NO: 1684) hCV2091644 C/TTTCTGGGGCATACAACG (SEQ ID NO: 1687) CTTCTGGGGCATACAACA (SEQ ID NO: 1688)AGGGACAACCCTCCATAAA (SEQ ID NO: 1689) hCV2121658 A/GAGTGGAGATTTAGCACCAGA (SEQ ID NO: 1690)GTGGAGATTTAGCACCAGG (SEQ ID NO: 1691)GTACATTTTGGATTGGGAGAGGATAT (SEQ ID NO: 1692) hCV2169762 G/TCGAGTCGGTCTGCTGC (SEQ ID NO: 1693) CGAGTCGGTCTGCTGA (SEQ ID NO: 1694)TGCCTACCTCATTCCATCTG (SEQ ID NO: 1695) hCV2192261 C/TCCTACCTTGAATTCACCTATCTG (SEQ IDCCTACCTTGAATTCACCTATCTA (SEQ ID NO: 1697)CATTTCCAAATCAGAAACATGA (SEQ ID NO: 1698) NO: 1696) hCV22275299 C/GGCAACTTGTTGAATGCCAG (SEQ ID NO: 1699)GCAACTTGTTGAATGCCAC (SEQ ID NO: 1700)GTGCTGTCACACCCAAGAAGTAC (SEQ ID NO: 1701) hCV2358247 A/GGGTTGGGCGTAAGGGTT (SEQ ID NO: 1702) GGTTGGGCGTAAGGGTC (SEQ ID NO: 1703)CCCTAGCTTTGCATAAATCATAC (SEQ ID NO: 1704) hCV2390937 A/CGTGGAAATGCAAGCTCTTCA (SEQ ID NO: 1705)TGGAAATGCAAGCTCTTCC (SEQ ID NO: 1706)CCAGATCGCTTTGGTAAAGGATTAA (SEQ ID NO: 1707) hCV2442143 C/TATTTAAGCATCATAGCATACCAC (SEQ IDATTTAAGCATCATAGCATACCAT (SEQ ID NO: 1 709)TGGTACACCATAAATCTTGACTTAC (SEQ ID NO: 1710) NO: 1708) hCV25473186 C/TATCTTCACAGTGTTCCACATC (SEQ ID NO: 1711)ATCTTCACAGTGTTCCACATT (SEQ ID NO: 1712)TTCTGACCTCCAGGTTCTTT (SEQ ID NO: 1713) hCV25596936 C/TGGCAGGCGAAGAGTCAC (SEQ ID NO: 1714) GGCAGGCGAAGAGTCAT (SEQ ID NO: 1715)GGGTCAATCCACAGTCTAGATG (SEQ ID NO: 1716) hCV25609987 A/GTGAGCAGGTAGCCTGTATTT (SEQ ID NO: 1717)TGAGCAGGTAGCCTGTATTC (SEQ ID NO: 1718)TGCTGCCTTGGTTGTGA (SEQ ID NO: 1719) hCV25615822 C/TCGGATCTTCTCCAGCG (SEQ ID NO: 1720) CCGGATCTTCTCCAGCA (SEQ ID NO: 1721)TGAAGCCACATCCTTCTTTAT (SEQ ID NO: 1722) hCV25623804 A/GTTTCAAGCTGTCTCCTACCAT (SEQ ID NO: 1723)TTTCAAGCTGTCTCCTACCAC (SEQ ID NO: 1724)GGAGAGAAGGGAAGGACTAAAG (SEQ ID NO: 1725) hCV25637605 A/GGCGGCTCTGCACAT (SEQ ID NO: 1726) GCGGCTCTGCACAC (SEQ ID NO: 1727)GCGGGTGGCTCCTTTAA (SEQ ID NO: 1728) hCV25651109 C/GGGTCCTGCTTGATGCG (SEQ ID NO: 1729) AGGTCCTGCTTGATGCC (SEQ ID NO: 1730)CGACCATGGACATTCACAT (SEQ ID NO: 1731) hCV25742059 A/GCTGCCTCTTCTGCATTAGA (SEQ ID NO: 1732)TGCCTCTTCTGCATTAGG (SEQ ID NO: 1733)CCTTCACTGCCTGTTTCTCT (SEQ ID NO: 1734) hCV25924894 A/GGGGAAGTTCTTTCTTGTATATTCAA (SEQ IDGGGAAGTTCTTTCTTGTATATTCAG (SEQ ID NO: 1736)TGCTGTCTTTGCCTCACTAAT (SEQ ID NO: 1737) NO: 1735) hCV25925481 A/GAATCAGCATTTTTGTCAAAGA (SEQ ID NO: 1738)ATCAGCATTTTTGTCAAAGG (SEQ ID NO: 1739)GGCTTGTGACCTCATTGTTT (SEQ ID NO: 1740) hCV25951678 A/GAATGCAGCTGCTCAAAGA (SEQ ID NO: 1741) ATGCAGCTGCTCAAAGG (SEQ ID NO: 1742)GTTCCCGGGCTCACA (SEQ ID NO: 1743) hCV25952089 A/CCCCTGCCTCTGTCTGACTA (SEQ ID NO: 1744)CCCTGCCTCTGTCTGACTC (SEQ ID NO: 1745)AAGACAAGCCCAGGTTCA (SEQ ID NO: 1746) hCV25983294 GTACCATCATTTACTCCTACCGC (SEQ ID NO: 1747)CCCATCATTTACTCCTACCGT (SEQ ID NO: 1748)GCCGAGCGGTCTGAG (SEQ ID NO: 1749) hCV2637554 C/TACATCCCAATAAAAGAGCAGG (SEQ ID NO: 1750)AAACATCCCAATAAAAGAGCAGA (SEQ ID NO: 1751)ACTTTGTTTCTTTCAGTATTTATGGCAGTGG (SEQ ID NO: 1752) hCV26478797 A/GGAAATCCTCCCACTGATGA (SEQ ID NO: 1753)AAATCCTCCCACTGATGG (SEQ ID NO: 1754)GCCAGATAGAATGACTTTATTGTAGA (SEQ ID NO: 1755) hCV26505812 A/GGTCAAATCTAAGCTGAGTGTTGA (SEQ ID TCAAATCTAAGCTGAGTGTTGG (SEQ ID NO: 1757)GCTTTCCCAGATGCACTGTATTGT (SEQ ID NO: 1758) NO: 1756) hCV26682080 A/GTCTCGGGTAGACCACACT (SEQ ID NO: 1759) CTCGGGTAGACCACACC (SEQ ID NO: 1760)GGCCCAGAGAGGTGAAGTTACT (SEQ ID NO: 1761) hCV26881276 A/GGAGTTGCTCACAAAAGGCA (SEQ ID NO: 1762)AGTTGCTCACAAAAGGCG (SEQ ID NO: 1763)GCAGGCCATGTGAATAGACATAC (SEQ ID NO: 1764) hCV27077072 C/TATCCTGGTATGGCCCC (SEQ ID NO: 1765) CATCCTGGTATGGCCCT (SEQ ID NO: 1766)GTCACACAAGCCAAGAAGAATTAGA (SEQ ID NO: 1767) hCV2741051 C/TGCAGCCAGTTTCTCCC (SEQ ID NO: 1768) TGCAGCCAGTTTCTCCT (SEQ ID NO: 1769)CATGAAATGCTTCCAGGTATT (SEQ ID NO: 1770) hCV27473671 C/TCTGACCTCCTGAATAATCCATC (SEQ ID NO: 1771)TCTGACCTCCTGAATAATCCATT (SEQ ID NO: 1772)CAGGGCTTCCCTAGCAGATAG (SEQ ID NO: 1773) hCV27494483 C/TAACAGCCATTCCTTGTCC (SEQ ID NO: 1774)GAACAGCCATTCCTTGTCT (SEQ ID NO: 1775)CCAGAAGCAGATGAAATGAGTAC (SEQ ID NO: 1776) hCV27504565 C/GGCTCCCAACACTGGACAG (SEQ ID NO: 1777)GCTCCCAACACTGGACAC (SEQ ID NO: 1778) GGTGGCAGAGCTCTCCT (SEQ ID NO: 1779)hCV27511436 C/T GGCCCCCATACATTACAAC (SEQ ID NO: 1780)GGCCCCCATACATTACAAT (SEQ ID NO: 1781)TGGAGGAAAGTTCTGGACAGTTA (SEQ ID NO: 1782) hCV2769503 A/GGGATTCGAGCCGACATCT (SEQ ID NO: 1783) GATTCGAGCCGACATCC (SEQ ID NO: 1784)TTGAGGATTAGCCTAGAACCACACA (SEQ ID NO: 1785) hCV27830265 A/GCGACCCATGAGAGAATCAGA (SEQ ID NO: 1786)CGACCCATGAGAGAATCAGG (SEQ ID NO: 1787)GCAGGTCCAGCCAGTGAA (SEQ ID NO: 1788) hCV27892569 C/TATGTGAAATTGCATGCACTTAG (SEQ ID NO: 1789)GTATGTGAAATTGCATGCACTTAA (SEQ ID NO: 1790)TGTGTGTACAACACCTATACATGTGTGT (SEQ ID NO: 1791) hCV28036404 A/TCATGAGACTCAACTTCTTAGGAAA (SEQ IDCATGAGACTCAACTTCTTAGGAAT (SEQ ID NO: 1793)GCACCAGCCAAGGTTTACTTTATAG (SEQ ID NO: 1794) NO: 1792) hCV2851380 C/GCTTGCTACCAATTCCATTTTCC (SEQ ID NO: 1795)CTTGCTACCAATTCCATTTTCG (SEQ ID NO: 1796)GGATCTCAGGGGCAAGTCTT (SEQ ID NO: 1797) hCV2862873 C/TTCAACAAATGTATTGATCAGCAAAC (SEQ IDCTCAACAAATGTATTGATCAGCAAAT (SEQ ID NO: 1799)CAGACAGGAGGAGTGGGATTCAT (SEQ ID NO: 1800) NO: 1798) hCV2930693 A/CGAAGAAGTACAACCCACAT (SEQ ID NO: 1801)GAAGAAGTACAACCCACAG (SEQ ID NO: 1802)GACACATGTAAGTTCCACTCATATG (SEQ ID NO: 1803) hCV29401764 C/TAAGGTGAGCTTGCCAATC (SEQ ID NO: 1804)AAGGTGAGCTTGCCAATT (SEQ ID NO: 1805)CATGGCGAGGAAGACACATAT (SEQ ID NO: 1806) hCV29480044 C/TGGTGGGCCTTTTGAAATAAAC (SEQ ID NO: 1807)TGGTGGGCCTTTTGAAATAAAT (SEQ ID NO: 1808)CTTGAAGTGAAGGCACCTGTCAT (SEQ ID NO: 1809) hCV29537898 C/TACCACAGCTGTCCCTC (SEQ ID NO: 1810) TACCACAGCTGTCCCTT (SEQ ID NO: 1811)GCCTCCCAGTGGGAATCT (SEQ ID NO: 1812) hCV29539757 A/CTCCAGTTAGGGATAAAGAAAGGA (SEQ ID CCAGTTAGGGATAAAGAAAGGC (SEQ ID NO: 1814)CCAGGCTGATCTCGAACTTCT (SEQ ID NO: 1815) NO: 1813) hCV29566897 C/TGAAGATAGATTCTGCCAAATCATTC (SEQ IDGAAGATAGATTCTGCCAAATCATTT (SEQ ID NO: 1817)GGTAAACTCCTGTTGCCTCAGTA (SEQ ID NO: 1818) NO: 1816) hCV2959482 A/GACACCTGCGGTTAGATTGA (SEQ ID NO: 1819)CACCTGCGGTTAGATTGG (SEQ ID NO: 1820)CGAAGCTTCACAGATGACATC (SEQ ID NO: 1821) hCV29881864 C/GCTTTCTTGACATCAGTGCTTC (SEQ ID NO: 1822)CTTTCTTGACATCAGTGCTTG (SEQ ID NO: 1823)CAAAGTCCTCCTTTTCCTTGACTCTG (SEQ ID NO: 1824) hCV302629 A/GAGCTGCTGCTTGCTAAATAT (SEQ ID NO: 1825)AGCTGCTGCTTGCTAAATAC (SEQ ID NO: 1826)CCTGGAAAGGTCATGCTACTCATACT (SEQ ID NO: 1827) hCV30308202 C/GTGGCAGGAGATGGATGTAC (SEQ ID NO: 1828)TGGCAGGAGATGGATGTAG (SEQ ID NO: 1829)CCAGTTACTTGACTTTTGGCGTTTCT (SEQ ID NO: 1830) hCV30454150 C/TTCTAGCAGATTTGTATCAGAACC (SEQ IDTAATCTAGCAGATTTGTATCAGAACT (SEQ ID NO: 1832)GCGACCCTCTCTGGTTAAACA (SEQ ID NO: 1833) NO: 1831) hCV3054550 C/TTCCTGTCTCTGTCCCTTTC (SEQ ID NO: 1834)ATCCTGTCTCTGTCCCTTTT (SEQ ID NO: 1835)CGGAGTGCCCTCTTGTCT (SEQ ID NO: 1836) hCV3054799 A/GTGACTCCCAGCATGAAT (SEQ ID NO: 1837) TGACTCCCAGCATGAAC (SEQ ID NO: 1838)TGGCTTATCAAGAGACATGAGA (SEQ ID NO: 1839) hCV3082219 A/GAGAGATAGTGGAAGCTTTGACA (SEQ ID NO: 1840)GAGATAGTGGAAGCTTTGACG (SEQ ID NO: 1841)CCTGCAGCACACTTTGTAATCTAC (SEQ ID NO: 1842) hCV31137507 C/GCCTGGGCAACAAAGTCAC (SEQ ID NO: 1843)CCTGGGCAACAAAGTCAG (SEQ ID NO: 1844)CAAGAATATTGGCCTGCTTCAAACTAG (SEQ ID NO: 1845) hCV31227848 C/TCCTTGGGGTAGTCCCC (SEQ ID NO: 1846) TCCTTGGGGTAGTCCCT (SEQ ID NO: 1847)GCTGGAGTCCCACTGAGA (SEQ ID NO: 1848) hCV31573621 C/TTGTAATTGGCCCAGAACAC (SEQ ID NO: 1849)ATGTAATTGGCCCAGAACAT (SEQ ID NO: 1850)CCTTCCAGGCTTCTCTCTGAT (SEQ ID NO: 1851) hCV31705214 A/TGTTGGTGAAGAAGGATTTGTAGT (SEQ IDGTTGGTGAAGAAGGATTTGTAGA (SEQ ID NO: 1853)GCTGGAAGCTTGACACTTGTTGAA (SEQ ID NO: 1854) NO: 1852) hCV32160712 A/TTGTGCCTTCCACATCTCA (SEQ ID NO: 1855)TGTGCCTTCCACATCTCT (SEQ ID NO: 1856)CAGGCTTTGGTCTGGGTTAAA (SEQ ID NO: 1857) hCV3216551 A/GGCATACATCACATTTTCTTTACCT (SEQ IDGCATACATCACATTTTCTTTACCC (SEQ ID NO: 1859)GTTCATTGCAGCATTTTCCCCAATAC (SEQ ID NO: 1860) NO: 1858) hCV323071 A/GAAACCAGGATATCAGAACATTTTA (SEQ IDACCAGGATATCAGAACATTTTG (SEQ ID NO: 1862)GGTCTTAGGAATTATCTGACATCTT (SEQ ID NO: 1863) NO: 1861) hCV435733 C/GCAACTACTCGGGAGACAG (SEQ ID NO: 1864)CAACTACTCGGGAGACAC (SEQ ID NO: 1865)CCTCTCAGCCCTCTCTCCATAAAG (SEQ ID NO: 1866) hCV454333 C/TGTATGGGCTTGAGGAAATCAC (SEQ ID NO: 1867)GTATGGGCTTGAGGAAATCAT (SEQ ID NO: 1868)TGCACAGATGGCTTCTGTATGT (SEQ ID NO: 1869) hCV540056 C/TAACTACTTCTGGATGGTCAGC (SEQ ID NO: 1870)AAACTACTTCTGGATGGTCAGT (SEQ ID NO: 1871)GGGTCCTGCAAGTAGACACTAAG (SEQ ID NO: 1872) hCV7425232 C/TTCAAAATTATTTCTTGCTACAGG (SEQ IDGTCAAAATTATTTCTTGCTACAGA (SEQ ID NO: 1874)TCCTCCAGCCTCTCATTC (SEQ ID NO: 1875) NO: 1873) hCV7917138 A/GCAGTAGCAATGGTAAAGATTTGAAT (SEQ IDCAGTAGCAATGGTAAAGATTTGAAC (SEQ ID NO: 1877)TTCCACTGTATAGACTCTCCTGTACAGAT (SEQ ID NO: 1876) NO: 1878) hCV8147903 A/GGGCTCTCTCGTGAGCA (SEQ ID NO: 1879) GGCTCTCTCGTGAGCG (SEQ ID NO: 1880)GAAGGGGCACAGTGCCTTTTAG (SEQ ID NO: 1881) hCV8754449 C/TGCAGCTGAGGATTTAGCAC (SEQ ID NO: 1882)GCAGCTGAGGATTTAGCAT (SEQ ID NO: 1883)CAGAGCAAGACCCTGTCTCTAA (SEQ ID NO: 1884) hCV8757333 C/TCGTCAGCTCCTTTTGACAC (SEQ ID NO: 1885)CGTCAGCTCCTTTTGACAT (SEQ ID NO: 1886)CCCCAGAGGGTCCAAATTTCT (SEQ ID NO: 1887) hCV8820007 A/TCTTGGATAGCCTGAACCAATAA (SEQ ID NO: 1888)CTTGGATAGCCTGAACCAATAT (SEQ ID NO: 1889)CGTGAATAGGGTCCAGAGTCTA (SEQ ID NO: 1890) hCV8942032 G/GTTTGGACATGGGCAAGC (SEQ ID NO: 1891) CTTTGGACATGGGCAAGG (SEQ ID NO: 1892)CCCTGCATGGAAAGGTAAGAAAGT (SEQ ID NO: 1893) hCV9296529 A/GCTCATCCTTAATATTGTTTACTTGTGAT (SEQ IDCTCATCCTTAATATTGTTTACTTGTGAC (SEQ ID NO: 1895CAAGACAGCCGCCTACAAGA (SEQ ID NO: 1896) NO: 1894 hCV9324316 C/TGCAGGGGTTTCTCACC (SEQ ID NO: 1897) TGCAGGGGTTTCTCACT (SEQ ID NO: 1898)CCCTCCGGCTCAATGTCA (SEQ ID NO: 1899) hCV9326822 C/TCTCGGGACCAGTCCAG (SEQ ID NO: 1900) CTCGGGACCAGTCCAA (SEQ ID NO: 1901)CCGACAGCCGAGGAGA (SEQ ID NO: 1902) hCV945276 G/TCGCCACAAACACATACCTG (SEQ ID NO: 1903)CGCCACAAACACATACCTT (SEQ ID NO: 1904) CCGCTGCTTGGAACAG (SEQ ID NO: 1905)hCV9473891 C/T AGACTTTGATGCCAACGAG (SEQ ID NO: 1906)CAGACTTTGATGCCAACGAA (SEQ ID NO: 1907)CCAAGCACATTTATTGAGCACTCAA (SEQ ID NO: 1908) hDV70959216 G/TCAAACAGTGATGCAAATCAATTTC (SEQ IDACAAACAGTGATGCAAATCAATTTA (SEQ ID NO: 1910)GAAGGGGGACGAAGAAGCTAGAA (SEQ ID NO: 1911) NO: 1909) hDV77718013 C/TGGGACCCTATAGGAGCTTC (SEQ ID NO: 1912)GGGACCCTATAGGAGCTTT (SEQ ID NO: 1913)TCATTCTTGGGGGAGAGGCTATTC (SEQ ID NO: 1914)

TABLE 4 Interrogated SNP Interrogated rs LD SNP LD SNP rs PowerThreshold r² r² hCV11548152 rs11580249 hCV30715059 rs12137135 0.510.477953358 0.4781 hCV11548152 rs11580249 hCV31574252 rs12128312 0.510.477953358 0.6764 hCV11738775 rs6754561 hCV27153776 rs10164837 0.510.66106443 0.8444 hCV11738775 rs6754561 hCV3232568 rs3795880 0.510.66106443 0.8552 hCV11758801 rs11841997 hCV30023295 rs9591381 0.510.58648249 1 hCV1408483 rs17070848 hCV1408479 rs12961976 0.510.685992147 0.8832 hCV1408483 rs17070848 hCV1408480 rs11663275 0.510.685992147 0.8379 hCV1408483 rs17070848 hCV1408481 rs11152374 0.510.685992147 0.8946 hCV1408483 rs17070848 hCV1408515 rs12967026 0.510.685992147 0.7306 hCV1408483 rs17070848 hCV29202466 rs7234941 0.510.685992147 0.8379 hCV1408483 rs17070848 hCV31494763 rs7242542 0.510.685992147 0.9429 hCV1408483 rs17070848 hCV31494861 rs12970840 0.510.685992147 0.8379 hCV15857769 rs2924914 hCV1379455 rs2942805 0.510.948384617 1 hCV15857769 rs2924914 hCV1379456 rs2978341 0.510.948384617 1 hCV15857769 rs2924914 hCV15857755 rs2924920 0.510.948384617 0.9584 hCV15857769 rs2924914 hCV15857780 rs2924912 0.510.948384617 0.9584 hCV15857769 rs2924914 hCV15878591 rs2978339 0.510.948384617 0.9594 hCV15857769 rs2924914 hCV15878604 rs2978352 0.510.948384617 0.9594 hCV15857769 rs2924914 hCV16167752 rs2930285 0.510.948384617 1 hCV15857769 rs2924914 hCV27184738 rs2942808 0.510.948384617 1 hCV15857769 rs2924914 hCV29765690 rs9644266 0.510.948384617 0.9582 hCV15879601 rs2275769 hCV11396361 rs9370261 0.510.394289193 0.6541 hCV15879601 rs2275769 hCV15879602 rs2275770 0.510.394289193 1 hCV15879601 rs2275769 hCV16113165 rs2792634 0.510.394289193 1 hCV15879601 rs2275769 hCV2140762 rs2792638 0.510.394289193 1 hCV15879601 rs2275769 hCV2140766 rs1340667 0.510.394289193 1 hCV15879601 rs2275769 hCV2140769 rs1150875 0.510.394289193 1 hCV15879601 rs2275769 hCV2140770 rs2792635 0.510.394289193 1 hCV15879601 rs2275769 hCV2140772 rs11963558 0.510.394289193 1 hCV15879601 rs2275769 hCV25929027 rs6934690 0.510.394289193 1 hCV15879601 rs2275769 hCV25930618 rs10484648 0.510.394289193 1 hCV15879601 rs2275769 hCV26548331 rs2145761 0.510.394289193 1 hCV15879601 rs2275769 hCV26548343 rs2754795 0.510.394289193 1 hCV15879601 rs2275769 hCV26548347 rs2754798 0.510.394289193 1 hCV15879601 rs2275769 hCV29161504 rs6914051 0.510.394289193 0.5561 hCV15879601 rs2275769 hCV29161551 rs6924913 0.510.394289193 1 hCV15879601 rs2275769 hCV29649198 rs9885975 0.510.394289193 1 hCV15879601 rs2275769 hCV29649199 rs9474772 0.510.394289193 1 hCV15879601 rs2275769 hCV29667033 rs9474754 0.510.394289193 1 hCV15879601 rs2275769 hCV29703373 rs9474766 0.510.394289193 1 hCV15879601 rs2275769 hCV29703374 rs9283919 0.510.394289193 1 hCV15879601 rs2275769 hCV29721486 rs9370254 0.510.394289193 0.5549 hCV15879601 rs2275769 hCV29721492 rs9474762 0.510.394289193 1 hCV15879601 rs2275769 hCV29811423 rs10484647 0.510.394289193 1 hCV15879601 rs2275769 hCV29902056 rs9464034 0.510.394289193 1 hCV15879601 rs2275769 hCV30082095 rs9357788 0.510.394289193 0.5896 hCV15879601 rs2275769 hCV30136287 rs9367551 0.510.394289193 0.5567 hCV15879601 rs2275769 hCV30154225 rs10155669 0.510.394289193 1 hCV15879601 rs2275769 hCV30190199 rs9474748 0.510.394289193 0.7432 hCV15879601 rs2275769 hCV30225881 rs9370259 0.510.394289193 0.5567 hCV15879601 rs2275769 hCV30225882 rs9283918 0.510.394289193 0.5567 hCV15879601 rs2275769 hCV30298175 rs9382281 0.510.394289193 0.5567 hCV15879601 rs2275769 hCV30298180 rs10080252 0.510.394289193 1 hCV15879601 rs2275769 hCV30370722 rs9942457 0.510.394289193 1 hCV15879601 rs2275769 hCV30370723 rs9474771 0.510.394289193 1 hCV15879601 rs2275769 hCV30388486 rs9382285 0.510.394289193 0.6552 hCV15879601 rs2275769 hCV30424487 rs9296737 0.510.394289193 0.5553 hCV15879601 rs2275769 hCV30514288 rs10484649 0.510.394289193 1 hCV15879601 rs2275769 hCV30586618 rs4329099 0.510.394289193 1 hCV15879601 rs2275769 hCV31341134 rs10948793 0.510.394289193 0.5567 hCV15879601 rs2275769 hCV31341182 rs11969948 0.510.394289193 1 hCV15879601 rs2275769 hCV31341185 rs9474746 0.510.394289193 1 hCV15879601 rs2275769 hCV31341188 rs6905950 0.510.394289193 1 hCV15879601 rs2275769 hCV31341214 rs9474774 0.510.394289193 1 hCV15879601 rs2275769 hCV3248104 rs1340664 0.510.394289193 1 hCV15879601 rs2275769 hCV3248105 rs7751241 0.510.394289193 1 hCV15879601 rs2275769 hCV7807314 rs9382274 0.510.394289193 0.5564 hCV15879601 rs2275769 hCV7807316 rs9357783 0.510.394289193 0.5567 hCV15879601 rs2275769 hCV7807392 rs9349691 0.510.394289193 0.5567 hCV15879601 rs2275769 hCV7807393 rs9349692 0.510.394289193 0.6541 hCV15879601 rs2275769 hCV7807402 rs1325821 0.510.394289193 0.5567 hCV15879601 rs2275769 hCV7807421 rs9395899 0.510.394289193 0.7931 hCV15879601 rs2275769 hCV7807440 rs12662586 0.510.394289193 0.7931 hCV15879601 rs2275769 hCV8767722 rs1342831 0.510.394289193 1 hCV15879601 rs2275769 hCV8768817 rs1325833 0.510.394289193 0.5567 hCV15879601 rs2275769 hCV8768819 rs991199 0.510.394289193 0.5564 hCV15879601 rs2275769 hCV8768954 rs1150884 0.510.394289193 1 hCV15879601 rs2275769 hCV8768992 rs1299293 0.510.394289193 1 hCV15879601 rs2275769 hCV8769017 rs1150874 0.510.394289193 1 hCV15879601 rs2275769 hCV8769025 rs1340665 0.510.394289193 1 hCV15879601 rs2275769 hDV70700190 rs16869492 0.510.394289193 1 hCV15879601 rs2275769 hDV70710884 rs16884761 0.510.394289193 1 hCV15879601 rs2275769 hDV70711006 rs16884943 0.510.394289193 1 hCV15879601 rs2275769 hDV70711009 rs16884946 0.510.394289193 1 hCV15879601 rs2275769 hDV70711130 rs16885091 0.510.394289193 1 hCV15879601 rs2275769 hDV71001425 rs17755375 0.510.394289193 1 hCV15879601 rs2275769 hDV77036921 rs4715443 0.510.394289193 0.7436 hCV16134786 rs2857595 hCV15896673 rs2596430 0.510.570810789 0.6215 hCV16134786 rs2857595 hCV26778946 rs2734583 0.510.570810789 0.6706 hCV16134786 rs2857595 hCV27300892 rs2922994 0.510.570810789 0.6198 hCV16134786 rs2857595 hCV27300895 rs2156874 0.510.570810789 0.6215 hCV16134786 rs2857595 hCV27301030 rs2844531 0.510.570810789 0.5926 hCV16134786 rs2857595 hCV27301032 rs2596565 0.510.570810789 0.6215 hCV16134786 rs2857595 hCV27452303 rs3094005 0.510.570810789 0.6706 hCV16134786 rs2857595 hCV27455402 rs3099844 0.510.570810789 0.6706 hCV16134786 rs2857595 hCV27462380 rs3130614 0.510.570810789 0.6592 hCV16134786 rs2857595 hCV27463679 rs3132472 0.510.570810789 0.6706 hCV16134786 rs2857595 hCV30109416 rs4143332 0.510.570810789 0.6084 hCV16134786 rs2857595 hCV30127488 rs3132473 0.510.570810789 0.7159 hCV16134786 rs2857595 hCV30319025 rs3093988 0.510.570810789 0.95 hCV16134786 rs2857595 hCV30589567 rs3093975 0.510.570810789 0.9498 hCV16134786 rs2857595 hCV50000055 rs1800629 0.510.570810789 0.8562 hCV16134786 rs2857595 hDV75435585 rs3134792 0.510.570810789 0.6582 hCV16336 rs362277 hCV1084102 rs363141 0.510.668699498 0.83 hCV16336 rs362277 hCV1084108 rs363100 0.51 0.6686994980.8413 hCV16336 rs362277 hCV1084110 rs363101 0.51 0.668699498 0.8413hCV16336 rs362277 hCV1084117 rs363106 0.51 0.668699498 0.8413 hCV16336rs362277 hCV11764409 rs6834455 0.51 0.668699498 0.8413 hCV16336 rs362277hCV11764411 rs6843895 0.51 0.668699498 0.8413 hCV16336 rs362277hCV2229297 rs362303 0.51 0.668699498 0.6732 hCV16336 rs362277 hCV2229306rs362310 0.51 0.668699498 0.8413 hCV16336 rs362277 hCV2231776 rs3630910.51 0.668699498 0.8413 hCV16336 rs362277 hCV2231787 rs363124 0.510.668699498 0.8176 hCV16336 rs362277 hCV2231788 rs363125 0.510.668699498 0.8413 hCV16336 rs362277 hCV2231789 rs363093 0.510.668699498 0.8413 hCV16336 rs362277 hCV2231797 rs363095 0.510.668699498 0.8023 hCV16336 rs362277 hCV2231805 rs363097 0.510.668699498 0.8413 hCV16336 rs362277 hCV2231808 rs363098 0.510.668699498 0.8413 hCV16336 rs362277 hCV2231925 rs362274 0.510.668699498 0.8911 hCV16336 rs362277 hCV2231935 rs362276 0.510.668699498 0.8413 hCV16336 rs362277 hCV2231937 rs362323 0.510.668699498 0.8486 hCV16336 rs362277 hCV2231938 rs362325 0.510.668699498 1 hCV16336 rs362277 hCV2231953 rs362338 0.51 0.6686994980.8413 hCV16336 rs362277 hCV2484952 rs363094 0.51 0.668699498 0.8413hCV16336 rs362277 hCV29284939 rs6839081 0.51 0.668699498 0.8413 hCV16336rs362277 hCV29284940 rs6446725 0.51 0.668699498 0.8413 hCV16336 rs362277hCV29284943 rs6839274 0.51 0.668699498 0.8413 hCV16336 rs362277hCV29726333 rs10021254 0.51 0.668699498 0.8413 hCV16336 rs362277hCV29816351 rs10155264 0.51 0.668699498 0.8413 hCV16336 rs362277hCV30627341 rs10488840 0.51 0.668699498 0.7513 hCV16336 rs362277hCV31758114 rs7688390 0.51 0.668699498 0.8413 hCV16336 rs362277hCV3266236 rs7654034 0.51 0.668699498 0.8413 hCV16336 rs362277hCV3266250 rs7665816 0.51 0.668699498 0.8413 hCV16336 rs362277hDV70681393 rs16844026 0.51 0.668699498 0.8413 hCV16336 rs362277hDV70681394 rs16844028 0.51 0.668699498 0.8413 hCV16336 rs362277hDV71057631 rs7683309 0.51 0.668699498 0.8294 hCV1958451 rs2985822hCV11288054 rs3008858 0.51 0.59989501 1 hCV1958451 rs2985822 hCV11288055rs1886686 0.51 0.59989501 1 hCV1958451 rs2985822 hCV11728590 rs20650020.51 0.59989501 0.6298 hCV1958451 rs2985822 hCV11731325 rs1925411 0.510.59989501 1 hCV1958451 rs2985822 hCV118052 rs6673462 0.51 0.599895010.9559 hCV1958451 rs2985822 hCV11863077 rs12137403 0.51 0.59989501 1hCV1958451 rs2985822 hCV11864627 rs4620509 0.51 0.59989501 1 hCV1958451rs2985822 hCV11864638 rs4486425 0.51 0.59989501 0.6247 hCV1958451rs2985822 hCV12102654 rs1925413 0.51 0.59989501 1 hCV1958451 rs2985822hCV1464018 rs2985826 0.51 0.59989501 1 hCV1958451 rs2985822 hCV1464019rs2985825 0.51 0.59989501 1 hCV1958451 rs2985822 hCV15755638 rs30088530.51 0.59989501 1 hCV1958451 rs2985822 hCV15755654 rs3008871 0.510.59989501 1 hCV1958451 rs2985822 hCV16119992 rs2815349 0.51 0.599895010.6298 hCV1958451 rs2985822 hCV16120003 rs2815359 0.51 0.59989501 1hCV1958451 rs2985822 hCV16120009 rs2815361 0.51 0.59989501 1 hCV1958451rs2985822 hCV16120017 rs2815370 0.51 0.59989501 1 hCV1958451 rs2985822hCV16120018 rs2815371 0.51 0.59989501 1 hCV1958451 rs2985822 hCV16186149rs2985797 0.51 0.59989501 1 hCV1958451 rs2985822 hCV16186183 rs21821430.51 0.59989501 1 hCV1958451 rs2985822 hCV16186204 rs2985821 0.510.59989501 1 hCV1958451 rs2985822 hCV16186205 rs2985824 0.51 0.599895011 hCV1958451 rs2985822 hCV16286251 rs2755256 0.51 0.59989501 1hCV1958451 rs2985822 hCV1958424 rs1925408 0.51 0.59989501 1 hCV1958451rs2985822 hCV1958425 rs1925409 0.51 0.59989501 0.6298 hCV1958451rs2985822 hCV1958426 rs1925410 0.51 0.59989501 0.6141 hCV1958451rs2985822 hCV1958427 rs1118392 0.51 0.59989501 0.6632 hCV1958451rs2985822 hCV1958436 rs3008854 0.51 0.59989501 1 hCV1958451 rs2985822hCV1958439 rs4655658 0.51 0.59989501 1 hCV1958451 rs2985822 hCV1958440rs3736905 0.51 0.59989501 0.6247 hCV1958451 rs2985822 hCV1958441rs3929738 0.51 0.59989501 0.6298 hCV1958451 rs2985822 hCV1958444rs2985818 0.51 0.59989501 1 hCV1958451 rs2985822 hCV1958449 rs15708380.51 0.59989501 0.6298 hCV1958451 rs2985822 hCV1958456 rs10789219 0.510.59989501 0.6298 hCV1958451 rs2985822 hCV1958457 rs2025608 0.510.59989501 1 hCV1958451 rs2985822 hCV2142099 rs2065000 0.51 0.59989501 1hCV1958451 rs2985822 hCV2142100 rs2755253 0.51 0.59989501 0.9196hCV1958451 rs2985822 hCV2142101 rs2755254 0.51 0.59989501 0.6247hCV1958451 rs2985822 hCV2142106 rs2755271 0.51 0.59989501 0.6182hCV1958451 rs2985822 hCV2142112 rs2815351 0.51 0.59989501 1 hCV1958451rs2985822 hCV2142114 rs2755242 0.51 0.59989501 0.6379 hCV1958451rs2985822 hCV2142122 rs2755244 0.51 0.59989501 1 hCV1958451 rs2985822hCV2142125 rs2065001 0.51 0.59989501 1 hCV1958451 rs2985822 hCV2142126rs2755245 0.51 0.59989501 1 hCV1958451 rs2985822 hCV2142127 rs27552460.51 0.59989501 1 hCV1958451 rs2985822 hCV2142133 rs2815360 0.510.59989501 0.6273 hCV1958451 rs2985822 hCV2142134 rs2755250 0.510.59989501 1 hCV1958451 rs2985822 hCV2142135 rs2755251 0.51 0.599895010.6298 hCV1958451 rs2985822 hCV2142137 rs2815363 0.51 0.59989501 0.6467hCV1958451 rs2985822 hCV2142138 rs1535365 0.51 0.59989501 0.6298hCV1958451 rs2985822 hCV2142160 rs2815380 0.51 0.59989501 0.7025hCV1958451 rs2985822 hCV2142162 rs1024229 0.51 0.59989501 0.7254hCV1958451 rs2985822 hCV2142163 rs1024230 0.51 0.59989501 0.7254hCV1958451 rs2985822 hCV2142165 rs2208577 0.51 0.59989501 0.6618hCV1958451 rs2985822 hCV26465724 rs12044278 0.51 0.59989501 1 hCV1958451rs2985822 hCV26465735 rs12131222 0.51 0.59989501 1 hCV1958451 rs2985822hCV27868373 rs4582760 0.51 0.59989501 0.6141 hCV1958451 rs2985822hCV27996044 rs4655662 0.51 0.59989501 0.6298 hCV1958451 rs2985822hCV287782 rs11208979 0.51 0.59989501 1 hCV1958451 rs2985822 hCV30441499rs4655663 0.51 0.59989501 1 hCV1958451 rs2985822 hCV3144208 rs9127970.51 0.59989501 1 hCV1958451 rs2985822 hCV3144211 rs2985794 0.510.59989501 1 hCV1958451 rs2985822 hCV3144213 rs3008873 0.51 0.59989501 1hCV1958451 rs2985822 hCV3144214 rs2985795 0.51 0.59989501 1 hCV1958451rs2985822 hCV79872 rs12132532 0.51 0.59989501 1 hCV1958451 rs2985822hCV92092 rs12041926 0.51 0.59989501 1 hCV1958451 rs2985822 hCV9510886rs1137656 0.51 0.59989501 1 hCV1958451 rs2985822 hDV70961073 rs174978280.51 0.59989501 1 hCV2121658 rs1187332 hCV1050736 rs726433 0.510.493100715 0.8585 hCV2121658 rs1187332 hCV1050741 rs1001904 0.510.493100715 0.7897 hCV2121658 rs1187332 hCV1050742 rs1001905 0.510.493100715 0.7897 hCV2121658 rs1187332 hCV11868553 rs2378669 0.510.493100715 0.914 hCV2121658 rs1187332 hCV11930968 rs1837305 0.510.493100715 0.7769 hCV2121658 rs1187332 hCV16035227 rs2579375 0.510.493100715 0.7769 hCV2121658 rs1187332 hCV16094752 rs2378670 0.510.493100715 1 hCV2121658 rs1187332 hCV16094754 rs2799484 0.510.493100715 1 hCV2121658 rs1187332 hCV2121649 rs17087514 0.510.493100715 1 hCV2121658 rs1187332 hCV2121666 rs1187326 0.51 0.4931007150.5394 hCV2121658 rs1187332 hCV26567602 rs17087497 0.51 0.493100715 1hCV2121658 rs1187332 hCV26567643 rs1187370 0.51 0.493100715 0.5824hCV2121658 rs1187332 hCV29169653 rs7468983 0.51 0.493100715 0.8585hCV2121658 rs1187332 hCV29169655 rs7045967 0.51 0.493100715 1 hCV2121658rs1187332 hCV3237574 rs1211443 0.51 0.493100715 1 hCV2121658 rs1187332hCV3237587 rs1187333 0.51 0.493100715 1 hCV2121658 rs1187332 hCV3237592rs1147193 0.51 0.493100715 0.5562 hCV2121658 rs1187332 hCV7423840rs1443441 0.51 0.493100715 0.5299 hCV2121658 rs1187332 hCV7423871rs1209068 0.51 0.493100715 0.5284 hCV2121658 rs1187332 hCV7424026rs1307279 0.51 0.493100715 0.5562 hCV2121658 rs1187332 hCV7424033rs1659412 0.51 0.493100715 0.7897 hCV2121658 rs1187332 hCV7424042rs1147198 0.51 0.493100715 0.5562 hCV2121658 rs1187332 hCV7424057rs1147195 0.51 0.493100715 0.7897 hCV2121658 rs1187332 hCV7424077rs1201364 0.51 0.493100715 0.7897 hCV2121658 rs1187332 hCV7424082rs1659415 0.51 0.493100715 1 hCV2121658 rs1187332 hCV7424093 rs11471900.51 0.493100715 1 hCV2121658 rs1187332 hCV7424099 rs1332894 0.510.493100715 1 hCV2121658 rs1187332 hCV7424100 rs1332893 0.51 0.4931007150.8585 hCV2121658 rs1187332 hDV70859017 rs17087470 0.51 0.4931007150.8585 hCV2121658 rs1187332 hDV70859019 rs17087472 0.51 0.4931007150.8585 hCV2121658 rs1187332 hDV70859037 rs17087496 0.51 0.493100715 1hCV2358247 rs415989 hCV26338105 rs1013561 0.51 0.799037114 1 hCV2358247rs415989 hCV29881294 rs6073814 0.51 0.799037114 0.826 hCV2358247rs415989 hCV30007459 rs10485460 0.51 0.799037114 1 hCV2358247 rs415989hCV7499352 rs1516579 0.51 0.799037114 1 hCV2358247 rs415989 hDV70786842rs16990761 0.51 0.799037114 1 hCV2358247 rs415989 hDV72026194 rs8006830.51 0.799037114 1 hCV2390937 rs739719 hCV2390936 rs739718 0.510.633865259 1 hCV25473186 rs2880415 hCV11313256 rs1947069 0.510.877072532 1 hCV25473186 rs2880415 hCV11313258 rs1947067 0.510.877072532 1 hCV25473186 rs2880415 hCV16209365 rs2342652 0.510.877072532 1 hCV25473186 rs2880415 hCV26159412 rs2342653 0.510.877072532 1 hCV25473186 rs2880415 hCV29013151 rs7688639 0.510.877072532 1 hCV25473186 rs2880415 hCV29987400 rs4234915 0.510.877072532 1 hCV25473186 rs2880415 hCV30852132 rs7673498 0.510.877072532 1 hCV25473186 rs2880415 hCV7427258 rs1047214 0.510.877072532 1 hCV25473186 rs2880415 hCV7428282 rs1444792 0.510.877072532 1 hCV25473186 rs2880415 hCV7428284 rs1444799 0.510.877072532 1 hCV25596936 rs6967117 hCV25596967 rs7800937 0.51 0.97099611 hCV25596936 rs6967117 hCV485060 rs1804527 0.51 0.9709961 1 hCV25983294rs3739709 hCV1316797 rs1043128 0.51 0.483483129 0.9447 hCV25983294rs3739709 hCV1316809 rs12555590 0.51 0.483483129 0.8857 hCV25983294rs3739709 hCV27503139 rs3936868 0.51 0.483483129 0.7051 hCV25983294rs3739709 hCV27883057 rs4978964 0.51 0.483483129 0.5049 hCV25983294rs3739709 hCV31956059 rs10980596 0.51 0.483483129 0.5434 hCV25983294rs3739709 hCV31956067 rs10980602 0.51 0.483483129 0.6012 hCV25983294rs3739709 hCV31956070 rs10980605 0.51 0.483483129 0.6847 hCV25983294rs3739709 hCV31956071 rs10980607 0.51 0.483483129 0.898 hCV25983294rs3739709 hCV31956076 rs10817101 0.51 0.483483129 0.6835 hCV25983294rs3739709 hCV31959065 rs10980575 0.51 0.483483129 0.7051 hCV25983294rs3739709 hCV613577 rs551517 0.51 0.483483129 0.6445 hCV25983294rs3739709 hCV8780367 rs1061548 0.51 0.483483129 1 hCV2637554 rs3205421hCV11704313 rs2041149 0.51 0.586104829 0.706 hCV2637554 rs3205421hCV11704321 rs1811338 0.51 0.586104829 0.6624 hCV2637554 rs3205421hCV2411030 rs741645 0.51 0.586104829 1 hCV2637554 rs3205421 hCV2637556rs2041150 0.51 0.586104829 0.5966 hCV2637554 rs3205421 hCV2637560rs9669539 0.51 0.586104829 1 hCV2637554 rs3205421 hCV2637565 rs108607790.51 0.586104829 1 hCV2637554 rs3205421 hCV2637574 rs730013 0.510.586104829 0.6624 hCV2637554 rs3205421 hCV2637576 rs3817305 0.510.586104829 1 hCV2637554 rs3205421 hCV2637583 rs4764813 0.51 0.5861048291 hCV2637554 rs3205421 hCV2637585 rs10492085 0.51 0.586104829 0.6624hCV2637554 rs3205421 hCV27278316 rs10778146 0.51 0.586104829 0.6395hCV2637554 rs3205421 hCV27480555 rs3764973 0.51 0.586104829 0.7373hCV2637554 rs3205421 hCV2905213 rs11832844 0.51 0.586104829 0.7378hCV2637554 rs3205421 hCV29407507 rs7957655 0.51 0.586104829 0.6624hCV2637554 rs3205421 hCV29407514 rs7960795 0.51 0.586104829 0.7391hCV2637554 rs3205421 hCV29407573 rs7965541 0.51 0.586104829 0.7373hCV2637554 rs3205421 hCV32176762 rs7135472 0.51 0.586104829 0.7602hCV2637554 rs3205421 hCV32176795 rs4764814 0.51 0.586104829 0.6624hCV2637554 rs3205421 hCV8698769 rs919214 0.51 0.586104829 0.6391hCV26478797 rs2015018 hCV2553995 rs10057898 0.51 0.783014529 0.8829hCV26478797 rs2015018 hCV2554001 rs6861345 0.51 0.783014529 0.8487hCV26478797 rs2015018 hCV2554006 rs1557759 0.51 0.783014529 0.8487hCV26478797 rs2015018 hCV2557450 rs42250 0.51 0.783014529 1 hCV26478797rs2015018 hCV29134287 rs6878107 0.51 0.783014529 0.7886 hCV26478797rs2015018 hCV30441646 rs6883532 0.51 0.783014529 0.8098 hCV27473671rs3750465 hCV11265714 rs12686736 0.51 0.86047945 1 hCV27473671 rs3750465hCV15849807 rs2900481 0.51 0.86047945 0.962 hCV27473671 rs3750465hCV15961264 rs2271878 0.51 0.86047945 0.962 hCV27473671 rs3750465hCV1751510 rs11789624 0.51 0.86047945 0.9259 hCV27473671 rs3750465hCV1751522 rs11792861 0.51 0.86047945 0.9259 hCV27473671 rs3750465hCV1751524 rs10512391 0.51 0.86047945 0.962 hCV27473671 rs3750465hCV1751537 rs11788825 0.51 0.86047945 0.962 hCV27473671 rs3750465hCV1751538 rs11794648 0.51 0.86047945 0.9259 hCV27473671 rs3750465hCV1751568 rs11788904 0.51 0.86047945 0.9207 hCV27473671 rs3750465hCV1751573 rs7870597 0.51 0.86047945 0.962 hCV27473671 rs3750465hCV25805845 rs3750451 0.51 0.86047945 0.962 hCV27473671 rs3750465hCV27507261 rs3829084 0.51 0.86047945 0.9259 hCV27473671 rs3750465hCV27511474 rs3750454 0.51 0.86047945 0.922 hCV27473671 rs3750465hCV29343287 rs7855282 0.51 0.86047945 0.962 hCV27473671 rs3750465hCV29343294 rs7470160 0.51 0.86047945 0.962 hCV27473671 rs3750465hCV8779898 rs1333344 0.51 0.86047945 0.962 hCV27473671 rs3750465hDV70967853 rs17552292 0.51 0.86047945 1 hCV27473671 rs3750465hDV70979148 rs17628095 0.51 0.86047945 1 hCV27473671 rs3750465hDV70997039 rs17729523 0.51 0.86047945 0.9617 hCV27473671 rs3750465hDV74776655 rs1044905 0.51 0.86047945 0.962 hCV27494483 rs3748743hCV12084456 rs1935829 0.51 0.567281167 0.5874 hCV27494483 rs3748743hCV12085551 rs1994830 0.51 0.567281167 1 hCV27494483 rs3748743hCV12085641 rs699753 0.51 0.567281167 0.881 hCV27494483 rs3748743hCV12085820 rs815124 0.51 0.567281167 0.881 hCV27494483 rs3748743hCV15752023 rs2995522 0.51 0.567281167 1 hCV27494483 rs3748743hCV16027831 rs2488452 0.51 0.567281167 1 hCV27494483 rs3748743hCV16052590 rs1689088 0.51 0.567281167 0.881 hCV27494483 rs3748743hCV16250228 rs2486081 0.51 0.567281167 1 hCV27494483 rs3748743hCV16250229 rs2486080 0.51 0.567281167 0.881 hCV27494483 rs3748743hCV25763709 rs2488429 0.51 0.567281167 1 hCV27494483 rs3748743hCV26680298 rs4839049 0.51 0.567281167 0.7078 hCV27494483 rs3748743hCV26680430 rs2488433 0.51 0.567281167 0.881 hCV27494483 rs3748743hCV26680450 rs2488449 0.51 0.567281167 1 hCV27494483 rs3748743hCV26681176 rs11810230 0.51 0.567281167 1 hCV27494483 rs3748743hCV29197202 rs1775518 0.51 0.567281167 1 hCV27494483 rs3748743hCV29723037 rs1775698 0.51 0.567281167 0.7927 hCV27494483 rs3748743hCV31476567 rs10923675 0.51 0.567281167 0.6429 hCV27494483 rs3748743hCV31476715 rs10923964 0.51 0.567281167 0.6807 hCV27494483 rs3748743hCV31477547 rs10923969 0.51 0.567281167 1 hCV27494483 rs3748743hCV31477571 rs10923965 0.51 0.567281167 1 hCV27494483 rs3748743hCV8690513 rs1342718 0.51 0.567281167 1 hCV27494483 rs3748743 hCV8690516rs1418656 0.51 0.567281167 0.8808 hCV27494483 rs3748743 hCV8690521rs1767265 0.51 0.567281167 0.881 hCV27494483 rs3748743 hCV8691661rs815105 0.51 0.567281167 0.881 hCV27494483 rs3748743 hCV8691672rs815107 0.51 0.567281167 0.881 hCV27494483 rs3748743 hCV8691697rs815118 0.51 0.567281167 0.881 hCV27494483 rs3748743 hCV8691711rs1281540 0.51 0.567281167 0.881 hCV27494483 rs3748743 hCV8692279rs1466812 0.51 0.567281167 0.8673 hCV27494483 rs3748743 hCV8692280rs815102 0.51 0.567281167 0.6071 hCV27494483 rs3748743 hCV8692287rs864175 0.51 0.567281167 0.7078 hCV27494483 rs3748743 hCV8692304rs1767259 0.51 0.567281167 1 hCV27494483 rs3748743 hCV8692310 rs17755190.51 0.567281167 0.7078 hCV27494483 rs3748743 hCV8692311 rs1767258 0.510.567281167 0.7078 hCV27494483 rs3748743 hCV8701061 rs1689087 0.510.567281167 0.7498 hCV27494483 rs3748743 hCV8701081 rs1775702 0.510.567281167 0.881 hCV27494483 rs3748743 hCV8701111 rs1281693 0.510.567281167 0.642 hCV27494483 rs3748743 hCV8701127 rs1798109 0.510.567281167 0.881 hCV27494483 rs3748743 hCV8701139 rs1798110 0.510.567281167 0.881 hCV27494483 rs3748743 hCV8701140 rs699768 0.510.567281167 0.881 hCV27494483 rs3748743 hCV8701141 rs1689096 0.510.567281167 0.8808 hCV27494483 rs3748743 hCV8701148 rs699766 0.510.567281167 0.7917 hCV27494483 rs3748743 hCV8701153 rs699765 0.510.567281167 0.8668 hCV27494483 rs3748743 hCV8701160 rs699761 0.510.567281167 0.881 hCV27494483 rs3748743 hCV8701179 rs699755 0.510.567281167 0.881 hCV27494483 rs3748743 hCV8701181 rs699754 0.510.567281167 1 hCV27494483 rs3748743 hCV8701183 rs699752 0.51 0.5672811670.881 hCV27494483 rs3748743 hCV8701197 rs699748 0.51 0.567281167 0.881hCV27494483 rs3748743 hCV8701213 rs1342719 0.51 0.567281167 0.881hCV27494483 rs3748743 hDV70820092 rs17034936 0.51 0.567281167 0.867hCV27494483 rs3748743 hDV70820421 rs17035363 0.51 0.567281167 0.6589hCV27504565 rs3219489 hCV148812 rs2153608 0.51 0.960429702 1 hCV27504565rs3219489 hCV16138635 rs2153609 0.51 0.960429702 1 hCV27504565 rs3219489hCV16154820 rs2185549 0.51 0.960429702 1 hCV27504565 rs3219489hCV16188158 rs2298018 0.51 0.960429702 1 hCV27504565 rs3219489hCV27913398 rs4660853 0.51 0.960429702 1 hCV27504565 rs3219489hCV27967653 rs4660854 0.51 0.960429702 1 hCV27504565 rs3219489hCV27968738 rs4660849 0.51 0.960429702 1 hCV27504565 rs3219489hCV27989232 rs4660852 0.51 0.960429702 1 hCV27504565 rs3219489hCV29054909 rs4520450 0.51 0.960429702 1 hCV27504565 rs3219489hCV29482894 rs9326141 0.51 0.960429702 1 hCV27504565 rs3219489hCV29609344 rs9429160 0.51 0.960429702 1 hCV27504565 rs3219489hCV29681797 rs9429072 0.51 0.960429702 1 hCV27504565 rs3219489hCV29736116 rs3219472 0.51 0.960429702 1 hCV27504565 rs3219489hCV30258653 rs9429076 0.51 0.960429702 1 hCV27504565 rs3219489hCV30456994 rs9429158 0.51 0.960429702 1 hCV27504565 rs3219489hCV30874754 rs11211101 0.51 0.960429702 1 hCV27504565 rs3219489hCV32304101 rs4660851 0.51 0.960429702 1 hCV27504565 rs3219489 hCV469305rs7543428 0.51 0.960429702 1 hCV27504565 rs3219489 hCV519782 rs24928400.51 0.960429702 1 hCV27511436 rs3750145 hCV106815 rs11771236 0.510.469307594 0.555 hCV27511436 rs3750145 hCV188768 rs10953041 0.510.469307594 0.653 hCV27511436 rs3750145 hCV27170501 rs12533378 0.510.469307594 0.7892 hCV27511436 rs3750145 hCV2835970 rs12540728 0.510.469307594 0.764 hCV27511436 rs3750145 hCV2835987 rs10953044 0.510.469307594 0.8598 hCV27511436 rs3750145 hCV29373899 rs7781027 0.510.469307594 0.686 hCV27511436 rs3750145 hCV32068681 rs11761729 0.510.469307594 0.8598 hCV27511436 rs3750145 hCV8315224 rs1052015 0.510.469307594 0.8598 hCV27511436 rs3750145 hDV72086373 rs34899057 0.510.469307594 0.8598 hCV2769503 rs4787956 hCV2769507 rs3024685 0.510.516261595 0.7057 hCV2769503 rs4787956 hCV8903080 rs1029489 0.510.516261595 0.7456 hCV2769503 rs4787956 hCV8903085 rs8832 0.510.516261595 0.5477 hCV2769503 rs4787956 hCV8903086 rs1049631 0.510.516261595 0.5278 hCV2769503 rs4787956 hDV70776992 rs16976728 0.510.516261595 0.7051 hCV27892569 rs4903741 hCV27198279 rs4903749 0.510.955713817 1 hCV27892569 rs4903741 hDV71062438 rs8006711 0.510.955713817 1 hCV2851380 rs12445805 hCV11667261 rs12446178 0.510.45310779 1 hCV2851380 rs12445805 hCV11667266 rs12448204 0.510.45310779 1 hCV2851380 rs12445805 hCV1565864 rs12447158 0.51 0.453107790.6364 hCV2851380 rs12445805 hCV26981883 rs12447735 0.51 0.45310779 1hCV2851380 rs12445805 hCV2851355 rs12446298 0.51 0.45310779 1 hCV2851380rs12445805 hCV2851356 rs12449083 0.51 0.45310779 0.8182 hCV2851380rs12445805 hCV2851359 rs12446840 0.51 0.45310779 1 hCV2851380 rs12445805hCV2851368 rs12447812 0.51 0.45310779 1 hCV2851380 rs12445805hCV29564089 rs9924583 0.51 0.45310779 0.5385 hCV2851380 rs12445805hCV31815677 rs12446340 0.51 0.45310779 1 hCV2851380 rs12445805hCV31815680 rs12448935 0.51 0.45310779 1 hCV2851380 rs12445805hCV31815681 rs12448739 0.51 0.45310779 1 hCV2851380 rs12445805hCV31815709 rs12927043 0.51 0.45310779 0.5898 hCV29537898 rs6073804hCV2358247 rs415989 0.51 0.552444046 0.7016 hCV29537898 rs6073804hCV26338105 rs1013561 0.51 0.552444046 0.7016 hCV29537898 rs6073804hCV26534413 rs544055 0.51 0.552444046 0.6811 hCV29537898 rs6073804hCV27947632 rs4812932 0.51 0.552444046 1 hCV29537898 rs6073804hCV27947633 rs4812930 0.51 0.552444046 1 hCV29537898 rs6073804hCV27947636 rs4812923 0.51 0.552444046 1 hCV29537898 rs6073804hCV29610044 rs6073808 0.51 0.552444046 1 hCV29537898 rs6073804hCV29827054 rs6073795 0.51 0.552444046 1 hCV29537898 rs6073804hCV29881294 rs6073814 0.51 0.552444046 0.8494 hCV29537898 rs6073804hCV29899344 rs4812922 0.51 0.552444046 1 hCV29537898 rs6073804hCV29935270 rs6073796 0.51 0.552444046 1 hCV29537898 rs6073804hCV30007459 rs10485460 0.51 0.552444046 0.7016 hCV29537898 rs6073804hCV30133494 rs6073819 0.51 0.552444046 1 hCV29537898 rs6073804hCV30169599 rs6073794 0.51 0.552444046 1 hCV29537898 rs6073804hCV30187505 rs6065834 0.51 0.552444046 0.6134 hCV29537898 rs6073804hCV30241248 rs6073789 0.51 0.552444046 1 hCV29537898 rs6073804hCV30259333 rs10485458 0.51 0.552444046 1 hCV29537898 rs6073804hCV30259338 rs6073797 0.51 0.552444046 1 hCV29537898 rs6073804hCV30277376 rs6073810 0.51 0.552444046 1 hCV29537898 rs6073804hCV30349417 rs6032347 0.51 0.552444046 0.6134 hCV29537898 rs6073804hCV30511464 rs6073791 0.51 0.552444046 1 hCV29537898 rs6073804hCV30529696 rs6073813 0.51 0.552444046 1 hCV29537898 rs6073804hCV30601833 rs6073793 0.51 0.552444046 1 hCV29537898 rs6073804hCV30601834 rs6073792 0.51 0.552444046 1 hCV29537898 rs6073804hCV7499352 rs1516579 0.51 0.552444046 0.7016 hCV29537898 rs6073804hDV70786611 rs16990423 0.51 0.552444046 1 hCV29537898 rs6073804hDV70786630 rs16990452 0.51 0.552444046 1 hCV29537898 rs6073804hDV70786842 rs16990761 0.51 0.552444046 0.7016 hCV29537898 rs6073804hDV72026194 rs800683 0.51 0.552444046 0.6545 hCV29539757 rs10110659hCV16018696 rs2116465 0.51 0.486011754 0.5448 hCV29539757 rs10110659hCV1894171 rs2469505 0.51 0.486011754 0.5448 hCV29539757 rs10110659hCV1894196 rs9642905 0.51 0.486011754 0.5894 hCV29539757 rs10110659hCV29774726 rs10108362 0.51 0.486011754 0.8046 hCV29539757 rs10110659hCV29991301 rs10111409 0.51 0.486011754 0.5523 hCV29539757 rs10110659hCV30513298 rs9297840 0.51 0.486011754 0.8063 hCV29539757 rs10110659hCV31233524 rs10956635 0.51 0.486011754 0.6776 hCV29539757 rs10110659hCV3218376 rs959003 0.51 0.486011754 0.5698 hCV29539757 rs10110659hDV70983393 rs17652451 0.51 0.486011754 1 hCV302629 rs9284183hCV11491432 rs7992229 0.51 0.476125719 0.827 hCV302629 rs9284183hCV11697373 rs7332672 0.51 0.476125719 0.5308 hCV302629 rs9284183hCV16091979 rs2182885 0.51 0.476125719 0.4929 hCV302629 rs9284183hCV1619929 rs9300542 0.51 0.476125719 0.901 hCV302629 rs9284183hCV1619953 rs9517704 0.51 0.476125719 0.9036 hCV302629 rs9284183hCV1619954 rs912130 0.51 0.476125719 0.9514 hCV302629 rs9284183hCV1619955 rs912131 0.51 0.476125719 0.9036 hCV302629 rs9284183hCV1619962 rs1923895 0.51 0.476125719 0.9512 hCV302629 rs9284183hCV2028227 rs9517637 0.51 0.476125719 0.4953 hCV302629 rs9284183hCV2028228 rs9517638 0.51 0.476125719 0.9512 hCV302629 rs9284183hCV2028233 rs9517642 0.51 0.476125719 0.8581 hCV302629 rs9284183hCV2028235 rs9517644 0.51 0.476125719 0.9514 hCV302629 rs9284183hCV2028239 rs11069357 0.51 0.476125719 0.9473 hCV302629 rs9284183hCV2028241 rs2296860 0.51 0.476125719 0.9514 hCV302629 rs9284183hCV2028245 rs7995524 0.51 0.476125719 0.9496 hCV302629 rs9284183hCV26560448 rs7983491 0.51 0.476125719 0.9514 hCV302629 rs9284183hCV26560464 rs7335403 0.51 0.476125719 0.8573 hCV302629 rs9284183hCV2699349 rs7999348 0.51 0.476125719 0.9041 hCV302629 rs9284183hCV28038226 rs4772201 0.51 0.476125719 0.5153 hCV302629 rs9284183hCV29166806 rs7999077 0.51 0.476125719 0.4956 hCV302629 rs9284183hCV2950553 rs7322572 0.51 0.476125719 0.533 hCV302629 rs9284183hCV3042329 rs4511390 0.51 0.476125719 0.9457 hCV302629 rs9284183hCV3042331 rs2181502 0.51 0.476125719 0.9514 hCV302629 rs9284183hCV3042333 rs9517686 0.51 0.476125719 1 hCV302629 rs9284183 hCV3042336rs7339230 0.51 0.476125719 0.9514 hCV302629 rs9284183 hCV3042337rs7338726 0.51 0.476125719 0.9514 hCV302629 rs9284183 hCV3042339rs1887704 0.51 0.476125719 0.7119 hCV302629 rs9284183 hCV31358927rs9554573 0.51 0.476125719 0.9514 hCV302629 rs9284183 hCV31358982rs11842736 0.51 0.476125719 0.9465 hCV302629 rs9284183 hCV3193760rs9585021 0.51 0.476125719 0.9514 hCV302629 rs9284183 hCV3193775rs7338177 0.51 0.476125719 0.5308 hCV302629 rs9284183 hCV3193777rs7139964 0.51 0.476125719 0.9514 hCV302629 rs9284183 hCV3193779rs731955 0.51 0.476125719 0.5137 hCV302629 rs9284183 hCV3193781 rs9844770.51 0.476125719 0.509 hCV302629 rs9284183 hCV3193783 rs9513584 0.510.476125719 0.8558 hCV302629 rs9284183 hCV3193794 rs2296911 0.510.476125719 0.9514 hCV302629 rs9284183 hCV3193798 rs6491493 0.510.476125719 0.9514 hCV302629 rs9284183 hCV8698973 rs927989 0.510.476125719 0.8886 hCV302629 rs9284183 hDV70984009 rs17655647 0.510.476125719 0.9512 hCV30308202 rs9482985 hCV11200332 rs9492268 0.510.712481366 0.7376 hCV30308202 rs9482985 hCV11200405 rs6569582 0.510.712481366 1 hCV30308202 rs9482985 hCV11692112 rs1979404 0.510.712481366 1 hCV30308202 rs9482985 hCV15796613 rs2448013 0.510.712481366 1 hCV30308202 rs9482985 hCV15886692 rs2494937 0.510.712481366 1 hCV30308202 rs9482985 hCV15967216 rs2279165 0.510.712481366 0.955 hCV30308202 rs9482985 hCV16163318 rs2219787 0.510.712481366 1 hCV30308202 rs9482985 hCV1889342 rs899350 0.51 0.7124813661 hCV30308202 rs9482985 hCV1889343 rs1478800 0.51 0.712481366 0.7698hCV30308202 rs9482985 hCV1889344 rs9492240 0.51 0.712481366 1hCV30308202 rs9482985 hCV1889345 rs1382515 0.51 0.712481366 1hCV30308202 rs9482985 hCV1889346 rs2448012 0.51 0.712481366 1hCV30308202 rs9482985 hCV1889347 rs7751112 0.51 0.712481366 1hCV30308202 rs9482985 hCV1889348 rs17056825 0.51 0.712481366 0.8924hCV30308202 rs9482985 hCV1889349 rs9492243 0.51 0.712481366 1hCV30308202 rs9482985 hCV1889355 rs11751534 0.51 0.712481366 1hCV30308202 rs9482985 hCV1889357 rs11756052 0.51 0.712481366 0.955hCV30308202 rs9482985 hCV1889358 rs11758207 0.51 0.712481366 1hCV30308202 rs9482985 hCV1889359 rs9492248 0.51 0.712481366 0.9525hCV30308202 rs9482985 hCV1889367 rs2876021 0.51 0.712481366 1hCV30308202 rs9482985 hCV1889371 rs6925197 0.51 0.712481366 1hCV30308202 rs9482985 hCV1889378 rs9492271 0.51 0.712481366 0.7467hCV30308202 rs9482985 hCV1889383 rs265334 0.51 0.712481366 0.7778hCV30308202 rs9482985 hCV1889389 rs265332 0.51 0.712481366 0.7776hCV30308202 rs9482985 hCV1889390 rs265380 0.51 0.712481366 0.7778hCV30308202 rs9482985 hCV26000215 rs17056847 0.51 0.712481366 0.7765hCV30308202 rs9482985 hCV27442718 rs7744609 0.51 0.712481366 1hCV30308202 rs9482985 hCV27442721 rs10499150 0.51 0.712481366 1hCV30308202 rs9482985 hCV27480203 rs3778132 0.51 0.712481366 0.7698hCV30308202 rs9482985 hCV27480208 rs3778137 0.51 0.712481366 0.7391hCV30308202 rs9482985 hCV27480211 rs3778141 0.51 0.712481366 0.955hCV30308202 rs9482985 hCV27499807 rs3778134 0.51 0.712481366 1hCV30308202 rs9482985 hCV27499808 rs3778135 0.51 0.712481366 1hCV30308202 rs9482985 hCV29433849 rs6569585 0.51 0.712481366 0.955hCV30308202 rs9482985 hCV29433859 rs7756786 0.51 0.712481366 1hCV30308202 rs9482985 hCV29433860 rs7738316 0.51 0.712481366 1hCV30308202 rs9482985 hCV29496377 rs6569583 0.51 0.712481366 1hCV30308202 rs9482985 hCV29532686 rs9492262 0.51 0.712481366 0.7698hCV30308202 rs9482985 hCV30020211 rs9492237 0.51 0.712481366 1hCV30308202 rs9482985 hCV30056140 rs7748051 0.51 0.712481366 1hCV30308202 rs9482985 hCV30092368 rs9492241 0.51 0.712481366 1hCV30308202 rs9482985 hCV30092369 rs6941264 0.51 0.712481366 1hCV30308202 rs9482985 hCV30110237 rs9492245 0.51 0.712481366 0.955hCV30308202 rs9482985 hCV30128317 rs9492253 0.51 0.712481366 1hCV30308202 rs9482985 hCV30182412 rs9482989 0.51 0.712481366 0.9548hCV30308202 rs9482985 hCV30200320 rs6569584 0.51 0.712481366 0.955hCV30308202 rs9482985 hCV30308200 rs9492263 0.51 0.712481366 1hCV30308202 rs9482985 hCV30308204 rs9492238 0.51 0.712481366 0.9537hCV30308202 rs9482985 hCV30398657 rs9492247 0.51 0.712481366 0.955hCV30308202 rs9482985 hCV30452477 rs9492265 0.51 0.712481366 1hCV30308202 rs9482985 hCV30470292 rs9492234 0.51 0.712481366 1hCV30308202 rs9482985 hCV30506242 rs9492264 0.51 0.712481366 1hCV30308202 rs9482985 hCV30560754 rs9492254 0.51 0.712481366 1hCV30308202 rs9482985 hCV30632610 rs7762236 0.51 0.712481366 1hCV30308202 rs9482985 hCV32245443 rs12210504 0.51 0.712481366 0.7521hCV30308202 rs9482985 hCV32245454 rs6569586 0.51 0.712481366 1hCV30308202 rs9482985 hCV32245465 rs12179603 0.51 0.712481366 1hCV30308202 rs9482985 hCV8922745 rs1478804 0.51 0.712481366 1hCV30308202 rs9482985 hCV8922746 rs1478803 0.51 0.712481366 1hCV30308202 rs9482985 hCV8922755 rs1478802 0.51 0.712481366 1hCV30308202 rs9482985 hCV8922768 rs1478798 0.51 0.712481366 1hCV30308202 rs9482985 hCV8922785 rs1478793 0.51 0.712481366 1hCV30308202 rs9482985 hCV8922791 rs1478792 0.51 0.712481366 0.955hCV30308202 rs9482985 hCV8922793 rs1478808 0.51 0.712481366 0.9509hCV30308202 rs9482985 hCV923718 rs727183 0.51 0.712481366 1 hCV30308202rs9482985 hCV923730 rs265361 0.51 0.712481366 0.8035 hCV30308202rs9482985 hCV923731 rs265360 0.51 0.712481366 0.7371 hCV30308202rs9482985 hCV923753 rs265382 0.51 0.712481366 0.7778 hCV30308202rs9482985 hCV923754 rs265381 0.51 0.712481366 0.7778 hCV30308202rs9482985 hCV923758 rs265388 0.51 0.712481366 0.7778 hCV30308202rs9482985 hCV923759 rs265387 0.51 0.712481366 0.7778 hCV30308202rs9482985 hCV923761 rs265385 0.51 0.712481366 0.7778 hCV30308202rs9482985 hCV923762 rs265384 0.51 0.712481366 0.7778 hCV30308202rs9482985 hDV70836483 rs17056909 0.51 0.712481366 1 hCV30308202rs9482985 hDV71969667 rs7767990 0.51 0.712481366 0.955 hCV3054550rs1559599 hCV11208814 rs4896640 0.51 0.580062034 0.8025 hCV3054550rs1559599 hCV11208823 rs9403478 0.51 0.580062034 0.83 hCV3054550rs1559599 hCV1649763 rs11155286 0.51 0.580062034 0.6394 hCV3054550rs1559599 hCV1649764 rs11155287 0.51 0.580062034 0.6113 hCV3054550rs1559599 hCV1649774 rs11754096 0.51 0.580062034 0.8482 hCV3054550rs1559599 hCV1649776 rs4896633 0.51 0.580062034 0.8482 hCV3054550rs1559599 hCV1649777 rs11752523 0.51 0.580062034 0.8482 hCV3054550rs1559599 hCV1649778 rs11753048 0.51 0.580062034 0.8482 hCV3054550rs1559599 hCV1649779 rs11755477 0.51 0.580062034 0.8476 hCV3054550rs1559599 hCV1649780 rs4896636 0.51 0.580062034 0.8463 hCV3054550rs1559599 hCV1649781 rs4896637 0.51 0.580062034 0.8482 hCV3054550rs1559599 hCV1649782 rs9496565 0.51 0.580062034 0.8025 hCV3054550rs1559599 hCV1649784 rs11753012 0.51 0.580062034 0.8481 hCV3054550rs1559599 hCV1649785 rs967633 0.51 0.580062034 0.8482 hCV3054550rs1559599 hCV1649786 rs9376741 0.51 0.580062034 0.8463 hCV3054550rs1559599 hCV1649787 rs11754065 0.51 0.580062034 0.8482 hCV3054550rs1559599 hCV27888181 rs4896650 0.51 0.580062034 1 hCV3054550 rs1559599hCV27888182 rs4896635 0.51 0.580062034 0.8476 hCV3054550 rs1559599hCV27888183 rs4896634 0.51 0.580062034 0.8476 hCV3054550 rs1559599hCV27888184 rs4895606 0.51 0.580062034 0.8482 hCV3054550 rs1559599hCV27937623 rs4895607 0.51 0.580062034 0.8476 hCV3054550 rs1559599hCV28024244 rs4896653 0.51 0.580062034 0.6324 hCV3054550 rs1559599hCV2867272 rs11758932 0.51 0.580062034 1 hCV3054550 rs1559599hCV29604750 rs9390074 0.51 0.580062034 0.8482 hCV3054550 rs1559599hCV29930123 rs9496561 0.51 0.580062034 0.8482 hCV3054550 rs1559599hCV29947932 rs9496594 0.51 0.580062034 0.9498 hCV3054550 rs1559599hCV30146228 rs9403485 0.51 0.580062034 0.9438 hCV3054550 rs1559599hCV30217924 rs9399434 0.51 0.580062034 0.6673 hCV3054550 rs1559599hCV30272167 rs9390075 0.51 0.580062034 0.8476 hCV3054550 rs1559599hCV30344162 rs9390076 0.51 0.580062034 0.8482 hCV3054550 rs1559599hCV30398541 rs9285499 0.51 0.580062034 0.6394 hCV3054550 rs1559599hCV30524360 rs9403486 0.51 0.580062034 0.9498 hCV3054550 rs1559599hCV3054531 rs6937858 0.51 0.580062034 0.894 hCV3054550 rs1559599hCV3054542 rs9399439 0.51 0.580062034 1 hCV3054550 rs1559599 hCV3054556rs11751030 0.51 0.580062034 1 hCV3054550 rs1559599 hCV32241095rs11757293 0.51 0.580062034 1 hCV3054550 rs1559599 hCV32241106rs11753058 0.51 0.580062034 0.8737 hCV3054550 rs1559599 hCV32404557rs4896632 0.51 0.580062034 0.8482 hCV3054550 rs1559599 hCV7576514 rs99080.51 0.580062034 0.95 hCV3054550 rs1559599 hCV9783869 rs4896639 0.510.580062034 0.8476 hCV3082219 rs1884833 hCV1781515 rs13218371 0.510.822864328 1 hCV3082219 rs1884833 hCV1802750 rs13213246 0.510.822864328 0.9393 hCV3082219 rs1884833 hCV1802756 rs13216434 0.510.822864328 1 hCV3082219 rs1884833 hCV3082214 rs17208849 0.510.822864328 1 hCV3082219 rs1884833 hCV3082227 rs2180621 0.51 0.8228643281 hCV31137507 rs7660668 hCV11746020 rs1979605 0.51 0.891437139 1hCV31137507 rs7660668 hCV11746021 rs1979604 0.51 0.891437139 1hCV31137507 rs7660668 hCV15809632 rs2101476 0.51 0.891437139 1hCV31137507 rs7660668 hCV16072560 rs2130040 0.51 0.891437139 1hCV31137507 rs7660668 hCV26406027 rs4336288 0.51 0.891437139 1hCV31137507 rs7660668 hCV27941642 rs4865012 0.51 0.891437139 1hCV31137507 rs7660668 hCV29101714 rs6851971 0.51 0.891437139 1hCV31137507 rs7660668 hCV29101718 rs7665846 0.51 0.891437139 1hCV31137507 rs7660668 hCV29882171 rs9993599 0.51 0.891437139 1hCV31137507 rs7660668 hCV30440588 rs6554291 0.51 0.891437139 1hCV31137507 rs7660668 hCV30494157 rs10012559 0.51 0.891437139 1hCV31137507 rs7660668 hCV31137533 rs6853506 0.51 0.891437139 1hCV31137507 rs7660668 hCV31137546 rs11732481 0.51 0.891437139 0.9502hCV31137507 rs7660668 hCV31137548 rs6554290 0.51 0.891437139 0.9594hCV31137507 rs7660668 hCV31137562 rs6830728 0.51 0.891437139 1hCV31137507 rs7660668 hCV31137564 rs6842960 0.51 0.891437139 0.9183hCV31137507 rs7660668 hCV769774 rs550144 0.51 0.891437139 1 hCV31137507rs7660668 hCV8746676 rs880358 0.51 0.891437139 1 hCV31137507 rs7660668hCV8746701 rs6802 0.51 0.891437139 1 hCV31137507 rs7660668 hCV8746719rs1801260 0.51 0.891437139 1 hCV31137507 rs7660668 hCV8746730 rs112400.51 0.891437139 1 hCV31137507 rs7660668 hCV8746755 rs1021307 0.510.891437139 1 hCV31137507 rs7660668 hCV8746756 rs1021306 0.510.891437139 1 hCV31137507 rs7660668 hCV8746776 rs972446 0.51 0.8914371391 hCV31137507 rs7660668 hDV70995909 rs17722979 0.51 0.891437139 1hCV31137507 rs7660668 hDV71005355 rs17776975 0.51 0.891437139 1hCV31137507 rs7660668 hDV71953492 rs7698022 0.51 0.891437139 1hCV31137507 rs7660668 hDV75174888 rs17721497 0.51 0.891437139 1hCV31137507 rs7660668 hDV75209995 rs2070062 0.51 0.891437139 1hCV31227848 rs11809423 hCV11874240 rs12731266 0.51 0.290800579 0.2996hCV31227848 rs11809423 hCV15842490 rs2181276 0.51 0.290800579 0.355hCV31227848 rs11809423 hCV1654102 rs12740722 0.51 0.290800579 0.2996hCV31227848 rs11809423 hCV3056582 rs12757352 0.51 0.290800579 0.2996hCV31227848 rs11809423 hDV70662612 rs17363472 0.51 0.290800579 0.2988hCV31227848 rs11809423 hDV71039510 rs6600383 0.51 0.290800579 0.2996hCV31705214 rs12804599 hCV107313 rs10833000 0.51 0.618581044 0.8531hCV31705214 rs12804599 hCV11594063 rs11024880 0.51 0.618581044 0.7562hCV31705214 rs12804599 hCV1950266 rs11024863 0.51 0.618581044 1hCV31705214 rs12804599 hCV1950274 rs10833015 0.51 0.618581044 1hCV31705214 rs12804599 hCV1950287 rs12787111 0.51 0.618581044 1hCV31705214 rs12804599 hCV29267415 rs7948997 0.51 0.618581044 0.8406hCV31705214 rs12804599 hCV31705227 rs11024850 0.51 0.618581044 1hCV31705214 rs12804599 hCV31705248 rs7931749 0.51 0.618581044 0.8479hCV31705214 rs12804599 hDV74880995 rs10832987 0.51 0.618581044 0.6552hCV31705214 rs12804599 hDV74888902 rs11024797 0.51 0.618581044 0.8369hCV31705214 rs12804599 hDV75065597 rs12275926 0.51 0.618581044 0.8191hCV32160712 rs11079160 hCV11616144 rs11656978 0.51 0.436836227 0.6753hCV32160712 rs11079160 hCV1388786 rs11079157 0.51 0.436836227 0.6444hCV32160712 rs11079160 hCV1388790 rs955734 0.51 0.436836227 0.5822hCV32160712 rs11079160 hCV1388795 rs11651545 0.51 0.436836227 0.7495hCV32160712 rs11079160 hCV1388815 rs12453442 0.51 0.436836227 0.7267hCV32160712 rs11079160 hCV1388823 rs9895713 0.51 0.436836227 0.8877hCV32160712 rs11079160 hCV1388832 rs12453544 0.51 0.436836227 0.8868hCV32160712 rs11079160 hCV27267033 rs11079158 0.51 0.436836227 0.5822hCV32160712 rs11079160 hCV29495159 rs9903045 0.51 0.436836227 1hCV32160712 rs11079160 hCV30379482 rs9895210 0.51 0.436836227 0.8507hCV32160712 rs11079160 hCV32160720 rs11656169 0.51 0.436836227 0.5822hCV32160712 rs11079160 hCV32160723 rs11654125 0.51 0.436836227 0.6208hCV32160712 rs11079160 hCV7595955 rs1465353 0.51 0.436836227 0.7565hCV32160712 rs11079160 hCV7595964 rs2010671 0.51 0.436836227 1hCV32160712 rs11079160 hCV8675361 rs7223639 0.51 0.436836227 0.5555hCV32160712 rs11079160 hDV70999843 rs17746075 0.51 0.436836227 0.942hCV32160712 rs11079160 hDV70999855 rs17746146 0.51 0.436836227 1hCV32160712 rs11079160 hDV71012207 rs17818816 0.51 0.436836227 1hCV454333 rs10916581 hCV31711080 rs10916583 0.51 0.908108083 1 hCV540056rs346802 hCV31556699 rs12165049 0.51 0.491985177 1 hCV540056 rs346802hCV540057 rs346801 0.51 0.491985177 1 hCV540056 rs346802 hCV540061rs346816 0.51 0.491985177 1 hCV540056 rs346802 hCV540062 rs346817 0.510.491985177 1 hCV540056 rs346802 hCV540063 rs453116 0.51 0.491985177 1hCV540056 rs346802 hCV540071 rs443112 0.51 0.491985177 1 hCV540056rs346802 hCV540074 rs369654 0.51 0.491985177 0.8251 hCV540056 rs346802hCV7446926 rs495055 0.51 0.491985177 0.6606 hCV7917138 rs9822460hCV11538341 rs9848078 0.51 0.404318811 0.4871 hCV7917138 rs9822460hCV11538354 rs11708509 0.51 0.404318811 1 hCV7917138 rs9822460hCV11556848 rs4857380 0.51 0.404318811 0.9027 hCV7917138 rs9822460hCV130955 rs9862953 0.51 0.404318811 0.5658 hCV7917138 rs9822460hCV159392 rs1497530 0.51 0.404318811 1 hCV7917138 rs9822460 hCV246831rs7640341 0.51 0.404318811 0.6769 hCV7917138 rs9822460 hCV246832rs7640257 0.51 0.404318811 0.6769 hCV7917138 rs9822460 hCV26005059rs13093620 0.51 0.404318811 0.6769 hCV7917138 rs9822460 hCV26008835rs9821488 0.51 0.404318811 0.4212 hCV7917138 rs9822460 hCV26158969rs4630981 0.51 0.404318811 1 hCV7917138 rs9822460 hCV26158970 rs76165040.51 0.404318811 0.4212 hCV7917138 rs9822460 hCV26922520 rs9869161 0.510.404318811 0.5455 hCV7917138 rs9822460 hCV26922587 rs13069360 0.510.404318811 0.9026 hCV7917138 rs9822460 hCV26922590 rs7646920 0.510.404318811 0.6769 hCV7917138 rs9822460 hCV29281482 rs6439825 0.510.404318811 0.6202 hCV7917138 rs9822460 hCV29644396 rs9877169 0.510.404318811 0.4212 hCV7917138 rs9822460 hCV30212818 rs9826529 0.510.404318811 0.6346 hCV7917138 rs9822460 hCV30320887 rs9289589 0.510.404318811 0.6346 hCV7917138 rs9822460 hCV362321 rs9847827 0.510.404318811 0.4777 hCV7917138 rs9822460 hCV362323 rs13068323 0.510.404318811 0.5932 hCV7917138 rs9822460 hCV362326 rs9289587 0.510.404318811 0.9027 hCV7917138 rs9822460 hCV362328 rs6799469 0.510.404318811 0.9027 hCV7917138 rs9822460 hCV362329 rs9844815 0.510.404318811 0.9027 hCV7917138 rs9822460 hCV362331 rs13086478 0.510.404318811 0.6305 hCV7917138 rs9822460 hCV362335 rs6439823 0.510.404318811 0.6769 hCV7917138 rs9822460 hCV362337 rs7630351 0.510.404318811 0.6769 hCV7917138 rs9822460 hCV50572 rs11721164 0.510.404318811 0.5526 hCV7917138 rs9822460 hCV50573 rs10433345 0.510.404318811 0.5526 hCV7917138 rs9822460 hCV7917329 rs904143 0.510.404318811 0.6276 hCV7917138 rs9822460 hDV77184830 rs6796827 0.510.404318811 0.6769 hCV7917138 rs9822460 hDV77231044 rs7638805 0.510.404318811 0.6769 hCV8147903 rs680014 hCV11785233 rs2460397 0.510.400661237 1 hCV8147903 rs680014 hCV11788458 rs2460386 0.51 0.4006612371 hCV8147903 rs680014 hCV11788468 rs553352 0.51 0.400661237 1 hCV8147903rs680014 hCV11788533 rs4799084 0.51 0.400661237 0.6566 hCV8147903rs680014 hCV12091565 rs629084 0.51 0.400661237 0.5434 hCV8147903rs680014 hCV1731571 rs580675 0.51 0.400661237 1 hCV8147903 rs680014hCV26871521 rs12605631 0.51 0.400661237 1 hCV8147903 rs680014 hCV2744994rs2510276 0.51 0.400661237 1 hCV8147903 rs680014 hCV2745000 rs26807520.51 0.400661237 1 hCV8147903 rs680014 hCV2745001 rs1788659 0.510.400661237 1 hCV8147903 rs680014 hCV27516223 rs3786238 0.51 0.4006612370.7292 hCV8147903 rs680014 hCV27877725 rs4799077 0.51 0.400661237 0.8788hCV8147903 rs680014 hCV29779584 rs4799081 0.51 0.400661237 0.9183hCV8147903 rs680014 hCV3068685 rs3859321 0.51 0.400661237 0.7991hCV8147903 rs680014 hCV3068718 rs673590 0.51 0.400661237 1 hCV8147903rs680014 hCV3068726 rs685665 0.51 0.400661237 1 hCV8147903 rs680014hCV3068731 rs522723 0.51 0.400661237 0.9587 hCV8147903 rs680014hCV3068735 rs517479 0.51 0.400661237 1 hCV8147903 rs680014 hCV3068736rs485400 0.51 0.400661237 1 hCV8147903 rs680014 hCV3068738 rs503615 0.510.400661237 1 hCV8147903 rs680014 hCV3068739 rs603957 0.51 0.400661237 1hCV8147903 rs680014 hCV3068757 rs3826573 0.51 0.400661237 0.4225hCV8147903 rs680014 hCV3068760 rs585571 0.51 0.400661237 0.8509hCV8147903 rs680014 hCV805999 rs649763 0.51 0.400661237 1 hCV8147903rs680014 hCV806002 rs681631 0.51 0.400661237 1 hCV8147903 rs680014hCV806008 rs655609 0.51 0.400661237 0.8402 hCV8147903 rs680014 hCV806012rs671424 0.51 0.400661237 0.4335 hCV8147903 rs680014 hCV806021 rs6183420.51 0.400661237 0.4335 hCV8147903 rs680014 hCV8155000 rs605183 0.510.400661237 1 hCV8147903 rs680014 hCV8155010 rs570029 0.51 0.400661237 1hCV8147903 rs680014 hCV8155011 rs589394 0.51 0.400661237 1 hCV8147903rs680014 hCV8831345 rs529195 0.51 0.400661237 1 hCV8147903 rs680014hCV8831346 rs1239783 0.51 0.400661237 1 hCV8147903 rs680014 hCV8831352rs500795 0.51 0.400661237 0.4335 hCV8942032 rs1264352 hCV11196362rs3129820 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV11690723rs886424 0.51 0.674510346 0.9461 hCV8942032 rs1264352 hCV15885725rs2532923 0.51 0.674510346 0.8224 hCV8942032 rs1264352 hCV15947385rs2233980 0.51 0.674510346 0.7828 hCV8942032 rs1264352 hCV16027870rs2517578 0.51 0.674510346 0.8297 hCV8942032 rs1264352 hCV2437063rs3131060 0.51 0.674510346 0.9468 hCV8942032 rs1264352 hCV2437065rs3129985 0.51 0.674510346 0.9468 hCV8942032 rs1264352 hCV2437122rs3095337 0.51 0.674510346 0.7947 hCV8942032 rs1264352 hCV2437158rs2284174 0.51 0.674510346 0.8428 hCV8942032 rs1264352 hCV2452431rs3132625 0.51 0.674510346 0.6845 hCV8942032 rs1264352 hCV25606044rs7750641 0.51 0.674510346 0.6923 hCV8942032 rs1264352 hCV25606244rs3130247 0.51 0.674510346 0.7442 hCV8942032 rs1264352 hCV25966128rs9262135 0.51 0.674510346 0.7934 hCV8942032 rs1264352 hCV26544258rs1634726 0.51 0.674510346 0.7745 hCV8942032 rs1264352 hCV26546104rs8233 0.51 0.674510346 0.7955 hCV8942032 rs1264352 hCV26546345rs2535332 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV26546351rs2263298 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV27452306rs3094032 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV27452307rs3094036 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV27452310rs3094057 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV27452312rs3094061 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV27452313rs3094064 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV27452317rs3094034 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV27452321rs3094031 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV27452331rs3094086 0.51 0.674510346 0.8942 hCV8942032 rs1264352 hCV27452332rs3094035 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV27452369rs3094127 0.51 0.674510346 0.7955 hCV8942032 rs1264352 hCV27452387rs3094222 0.51 0.674510346 0.7571 hCV8942032 rs1264352 hCV27452568rs3094703 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV27452590rs3094717 0.51 0.674510346 0.6845 hCV8942032 rs1264352 hCV27452726rs3095329 0.51 0.674510346 0.7945 hCV8942032 rs1264352 hCV27452728rs3095336 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV27452739rs3095330 0.51 0.674510346 0.8339 hCV8942032 rs1264352 hCV27452751rs3095338 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV27452792rs3095153 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV27452821rs3095340 0.51 0.674510346 0.8428 hCV8942032 rs1264352 hCV27462338rs3130353 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV27462341rs3130374 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV27462390rs3130660 0.51 0.674510346 0.7934 hCV8942032 rs1264352 hCV27462600rs3131050 0.51 0.674510346 0.942 hCV8942032 rs1264352 hCV27462601rs3131064 0.51 0.674510346 0.9485 hCV8942032 rs1264352 hCV27462862rs3131788 0.51 0.674510346 0.7415 hCV8942032 rs1264352 hCV27462962rs3129812 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV27462963rs3129815 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV27462964rs3129818 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV27462981rs3129973 0.51 0.674510346 0.8435 hCV8942032 rs1264352 hCV27462982rs3129984 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV27462996rs3130123 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV27463014rs3130352 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV27463047rs3130782 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV27463445rs3131783 0.51 0.674510346 0.7423 hCV8942032 rs1264352 hCV27463454rs3131934 0.51 0.674510346 0.7955 hCV8942032 rs1264352 hCV27463630rs3130557 0.51 0.674510346 0.7415 hCV8942032 rs1264352 hCV27463637rs3130641 0.51 0.674510346 0.942 hCV8942032 rs1264352 hCV27463692rs3132580 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV27463694rs3132610 0.51 0.674510346 0.7442 hCV8942032 rs1264352 hCV27463813rs3131044 0.51 0.674510346 0.9447 hCV8942032 rs1264352 hCV27464298rs3132600 0.51 0.674510346 0.7998 hCV8942032 rs1264352 hCV27464300rs3132605 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV27464304rs3132630 0.51 0.674510346 0.6845 hCV8942032 rs1264352 hCV27464305rs3132631 0.51 0.674510346 0.6845 hCV8942032 rs1264352 hCV27464307rs3132645 0.51 0.674510346 0.7345 hCV8942032 rs1264352 hCV27465359rs3129978 0.51 0.674510346 0.8905 hCV8942032 rs1264352 hCV27465360rs3129980 0.51 0.674510346 0.942 hCV8942032 rs1264352 hCV27465386rs3130350 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV27465389rs3130364 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV27465407rs3130544 0.51 0.674510346 0.7218 hCV8942032 rs1264352 hCV27465417rs3130673 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV27465853rs3132634 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV27465855rs3132649 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV29486333rs3132584 0.51 0.674510346 0.7955 hCV8942032 rs1264352 hCV29504305rs3094712 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV29522452rs3095334 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV29540580rs3094067 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV29558680rs3132599 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV29594803rs9262204 0.51 0.674510346 0.9398 hCV8942032 rs1264352 hCV29666963rs3130363 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV29666973rs9262130 0.51 0.674510346 0.7768 hCV8942032 rs1264352 hCV29703261rs3095155 0.51 0.674510346 0.8696 hCV8942032 rs1264352 hCV29721426rs3132616 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV29775548rs3132647 0.51 0.674510346 0.6952 hCV8942032 rs1264352 hCV29847742rs3129809 0.51 0.674510346 0.7345 hCV8942032 rs1264352 hCV29883892rs3132581 0.51 0.674510346 0.8865 hCV8942032 rs1264352 hCV29992126rs3094627 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV29992140rs9262200 0.51 0.674510346 0.9468 hCV8942032 rs1264352 hCV30028026rs3130372 0.51 0.674510346 0.6845 hCV8942032 rs1264352 hCV30045930rs3095326 0.51 0.674510346 0.8435 hCV8942032 rs1264352 hCV30045931rs3131055 0.51 0.674510346 0.8951 hCV8942032 rs1264352 hCV30172261rs3130365 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV30190135rs3094621 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV30262083rs3094050 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV30262102rs3130665 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV30280013rs3094024 0.51 0.674510346 0.7442 hCV8942032 rs1264352 hCV30352101rs3129821 0.51 0.674510346 0.6845 hCV8942032 rs1264352 hCV30424437rs9262143 0.51 0.674510346 0.7934 hCV8942032 rs1264352 hCV30442461rs9262141 0.51 0.674510346 0.7768 hCV8942032 rs1264352 hCV30496055rs3130117 0.51 0.674510346 0.7442 hCV8942032 rs1264352 hCV30622443rs3129823 0.51 0.674510346 0.6845 hCV8942032 rs1264352 hCV3273752rs3130370 0.51 0.674510346 0.6845 hCV8942032 rs1264352 hCV7926405rs3130126 0.51 0.674510346 0.6961 hCV8942032 rs1264352 hCV8692767rs1264376 0.51 0.674510346 0.9468 hCV8942032 rs1264352 hCV8692768rs1264377 0.51 0.674510346 0.8951 hCV8942032 rs1264352 hCV8692796rs1059612 0.51 0.674510346 0.7934 hCV8942032 rs1264352 hCV8692806rs1064627 0.51 0.674510346 0.7955 hCV8942032 rs1264352 hCV8941738rs1634721 0.51 0.674510346 0.8435 hCV8942032 rs1264352 hCV8941879rs1264308 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV8941918rs1049633 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV8941930rs886422 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV8941940rs1264322 0.51 0.674510346 0.8905 hCV8942032 rs1264352 hCV8941988rs2535340 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV8942006rs1264341 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV8942015rs1264347 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV8942025rs1264349 0.51 0.674510346 0.8946 hCV8942032 rs1264352 hCV8942026rs1264350 0.51 0.674510346 0.8812 hCV8942032 rs1264352 hCV8942038rs1264353 0.51 0.674510346 0.9427 hCV8942032 rs1264352 hCV9481170rs886423 0.51 0.674510346 1 hCV8942032 rs1264352 hDV75255684 rs25175460.51 0.674510346 0.6985

TABLE 5 Baseline Characteristics of ARIC Participants in Ischemic StrokeStudy Whites (N = 10401) Blacks(N = 3814) Cases Non-cases CasesNon-cases (N = 275) (N = 10126) (N = 220) (N = 3594) CharacteristicsMean (SD) Mean (SD) p-value* Mean (SD) Mean (SD) p-value* Age 57.59(5.32) 54.10 (5.69) <0.01 55.21 (5.79) 53.25 (5.79) <0.01 Waist-to-hipratio  0.96 (0.07)  0.92 (0.08) <0.01  0.94 (0.07)  0.92 (0.08) <0.01 N(%) N (%) p-value* N (%) N (%) p-value* Male 162 (59) 4569 (45) <0.01 97 (44) 1318 (37) 0.03 Hypertensive 137 (50) 2516 (25) <0.01 168 (77)1903 (53) <0.01  Diabetic  55 (20)  799 (8)  <0.01  94 (44)  596 (17)<0.01  Smoker  90 (33) 2455 (24) <0.01  81 (37) 1036 (29) 0.01 *p-valuerepresents a comparison between cases and non-cases within an ethnicgroup

TABLE 6 SNPs Associated with Incident Ischemic Stroke in the ARIC StudyRisk- Risk- raising lowering Model 1^(†) Model 2^(‡) allele allele 95%p- 95% p- Gene Symbol SNP ID Function* (frequency) (frequency) HRR CIvalue HRR CI value Whites SERPINA9 rs11628722 Nonsynonymous G (0.84) A(0.16) 1.31 1.00-1.70 0.05 1.32 1.02-1.72 0.03 Ala348Val PALLD rs7439293Intronic A (0.62) G (0.38) 1.24 1.03-1.49 0.02 1.21 1.01-1.46 0.04 IER2rs1042164 Nonsynonymous T (0.17) C (0.83) 1.38 1.12-1.71 0.003 1.391.12-1.72  0.003 Val133Ala Blacks SERPINA9 rs11628722 Nonsynonymous G(0.45) A (0.55) 1.26 1.03-1.53 0.02 1.27 1.04-1.54 0.02 Ala348Val EXOD1rs3213646 Intronic C (0.16) T (0.84) 1.29 1.01-1.64 0.04 1.29 1.01-1.650.04 *First amino acid corresponds to risk raising allele fornonsynonymous SNPs. ^(†)Model 1 was adjusted for age and gender.^(‡)Model 2 was adjusted for age, gender, waist-to-hip ratio anddiabetes, hypertension and smoking status.

TABLE 7 p-value Risk White (two- Black p-value hCV number rs number GeneSymbol Allele HRR 95% CI sided) HRR 95% CI (two-sided) hCV2091644rs1010   VAMP8 C 1.16 0.97-1.38 0.1 0.9 0.74-1.10 0.3 hCV25925481rs11628722 SERPINA9 G 1.31 1.00-1.70 0.05 1.26 1.03-1.53 0.02 hCV323071rs7439293  PALLD A 1.24 1.03-1.49 0.02 1.2 0.93-1.56 0.16 hCV7425232rs3900940  MYH15 C 1.18 0.98-1.42 0.08 1.1 0.85-1.43 0.49 hCV9326822rs1042164  IER2 T 1.38 1.12-1.71 0 0.54 0.27-1.09 0.08 hCV15770510rs3027309  ALOX12B T 1.17 0.95-1.46 0.14 1.25 0.88-1.77 0.21 hCV9626088rs943133  LOC391102 A 1.13 0.94-1.36 0.19 1 0.69-1.45 1

TABLE 8 p-value Gene Risk White (two- Black p-value hCV number rs numberSymbol Allele HRR 95% CI sided) HRR 95% CI (two-sided) hCV25924894rs17090921 SERPINA9 A 1.12 0.93-1.35 0.23 1.19 0.92-1.52 0.18 hCV1690777rs12684749 NFIB G 0.99 0.64-1.53 0.97 1.68 0.90-3.13 0.1 hCV25925481rs11628722 SERPINA9 G 1.31 1.00-1.70 0.05 1.26 1.03-1.53 0.02 hCV323071rs7439293  PALLD A 1.24 1.03-1.49 0.02 1.2 0.93-1.56 0.16 hCV25609987rs10817479 WDR31 A 0.93 0.65-1.32 0.67 5.15  0.72-36.78 0.1 hCV2192261rs3213646  EXOD1 C 0.98 0.82-1.17 0.82 1.29 1.01-1.64 0.04

TABLE 9 p-value Risk White (two- Black p-value hCV number rs number GeneSymbol Allele HRR 95% CI sided) HRR 95% CI (two-sided) hCV25924894rs17090921 SERPINA9 A 1.12 0.93-1.35 0.23 1.19 0.92-1.52 0.18hCV25925481 rs11628722 SERPINA9 G 1.31 1.00-1.70 0.05 1.26 1.03-1.530.02 hCV323071 rs7439293  PALLD A 1.24 1.03-1.49 0.02 1.2 0.93-1.56 0.16

TABLE 10 Baseline Characteristics of CHS Participants in Ischemic StrokeStudy African Characteristic Whites Americans Number of individuals inthis analysis 3849 673 Male 1575 (41) 243 (36) Age, mean (SD), y  72.7(5.6) 72.9 (5.7) BMI, mean (SD), kg/m²  26.3 (4.5) 28.5 (5.6) Smoking,current  423 (11) 113 (17) Diabetes  511 (13) 151 (23) Impaired fastingglucose  522 (14)  92 (14) Hypertension 2110 (55) 490 (73) LDLcholesterol, mean (SD), mg/dL  130 (36) 129 (36) HDL cholesterol, mean(SD), mg/dL   54 (16)  58 (15) Total cholesterol, mean (SD), mg/dL  212(39) 210 (39) Data presented as number of participants (%) unlessotherwise indicated.

TABLE 11 SNPs Associated with Incident Ischemic Stroke in WhiteParticipants of CHS Prespecified Risk Allele Gene dbSNP Risk AlleleFrequency HR (90% CI)* P HPS1 rs1804689 T 0.30 1.23 (1.09-1.40) 0.003ITGAE rs220479 C 0.82 1.26 (1.08-1.48) 0.008 ABCG2 rs2231137 C 0.95 1.46(1.05-2.03) 0.03  MYH15 rs3900940 C 0.29 1.15 (1.02-1.31) 0.03  FSTL4rs13183672 A 0.76 1.17 (1.01-1.35) 0.04  CALM1 rs3814843 G 0.05 1.31(1.02-1.68) 0.04  BAT2 rs11538264 G 0.97 1.49 (1.02-2.16) 0.04  *Hazardratios (HR) are adjusted for baseline age, sex, body mass index, currentsmoking, diabetes, impaired fasting glucose, hypertension,LDL-cholesterol, and HDL-cholesterol at baseline. Hazard ratios are percopy of the risk allele.

TABLE 12 SNPs Associated with Incident Ischemic Stroke in AfricanAmerican Participants of CHS Pre- Risk specified Allele Gene dbSNP RiskAllele Frequency HR (90% CI)* P KRT4 rs89962 T 0.11 2.08 (1.48-2.94)<0.001 LY6G5B rs11758242 C 0.89 2.28 (1.20-4.33) 0.02 EDG1 rs2038366 G0.73 1.59 (1.08-2.35) 0.02 DMXL2 rs12102203 G 0.47 1.40 (1.03-1.90) 0.04ABCG2 rs2231137 C 0.95 3.59 (1.11-11.7) 0.04 *Hazard ratios (HR) areadjusted for baseline age, sex, body mass index, current smoking,diabetes, impaired fasting glucose, hypertension, LDL-cholesterol, andHDL-cholesterol at baseline. Hazard ratios are per copy of the riskallele.

TABLE 13 The Val Allele Homozygotes of ABCG2 Val12Met (rs2231137),Compared with the Met Allele Carriers, are Associated With IncreasedRisk of Incident Ischemic Stroke in Both White and African AmericanParticipants of CHS ABCG2 Events Total Model 1* Model 2* Genotype n n HR(90% CI) P HR (90% CI) P White ValVal 370 3398 1.58 (1.12-2.23) 0.021.50 (1.06-2.12) 0.03 ValMet + MetMet 24 335 1 (Reference) 1 (Reference)ValMet 23 321 MetMet 1 14 Af. Am. ValVal 66 592 3.80 (1.16-12.4) 0.033.62 (1.11-11.9) 0.04 ValMet + MetMet 2 70 1 (Reference) 1 (Reference)ValMet 2 69 MetMet 0 1 *Model 1 was adjusted for baseline age and sex.Model 2 was adjusted for baseline age, sex, body mass index, currentsmoking, diabetes, impaired fasting glucose, hypertension,LDL-cholesterol, and HDL-cholesterol.

TABLE 14 HR (90% CI) risk AgeSex p-value gene rs # hCV# allele mode(whites) (whites) CENPE rs2243682  hCV1624173  A dom  1.2 (1.02, 1.42)0.034 FCRLB rs34868416 hCV25951678 A rec 2.01 (1.07, 3.76) 0.034 FSTL4rs3749817  hCV25637605 G dom 2.04 (1.2, 3.45)  0.013 HR (90% CI) HR (90%CI) HR (90% CI) Full p-value AgeSex p-value Full p-value gene (whites)(whites) (blacks) (blacks) (blacks) (blacks) CENPE  1.2 (1.01, 1.42)0.037 .98 (.51, 1.9) 0.517 1.17 (.6, 2.28)  0.352 FCRLB 2.18 (1.16,4.09) 0.021 1.52 (.84, 2.74) 0.122 1.82 (.97, 3.44) 0.06  FSTL4 2.04(1.2, 3.46)  0.013 “HR (90% CI) AgeSex” = hazard ratio (with 90%confidence intervals) adjusted for age and sex “HR (90% CI) Full” =hazard ratio (with 90% confidence intervals fully adjusted for alltraditional risk factors including smoking, diabetes, hypertension,HDL-C, LDL-C, and BMI

TABLE 15 Characteristics of noncardioembolic stroke cases and healthycontrols in VSR Cases Controls Characteristics n = 562 n = 815 p Age(SD) 66.0 (14)   58.8 (8.5)   <0.0001 Male 326 (58.0) 397 (48.7) 0.0007Smoking 172 (32.0) 147 (18.7) <0.0001 Hypertension 400 (71.2) 403 (49.5)<0.0001 Diabetes 191 (34.0) 36 (4.4) <0.0001 Dyslipidemia 347 (61.7) 464(56.9) 0.07 BMI (SD) 26.8 (4.9)   26.0 (3.8)   0.004 Age and BMI arepresented as means (standard deviation, SD) Other risk factors arepresented as counts (%) having the risk factor

TABLE 16 Characteristics of six SNPs tested for association withnoncardioembolic stroke in VSR. CHD Risk Frequency in Frequency in GeneAllele VSR Controls ARIC Whites* Chrom Loc^(†) SNP ID SNP Type SNPSource MYH15 C 0.29 0.30 3q13.13 rs3900940  Thr1125Ala Bare et al KIF6 G0.37 0.36 6p21.2 rs20455   Trp719Arg Bare et al VAMP8 C 0.38 0.42 2p12rs1010   3′UTR Bare et al Chr9p21 G 0.46 0.49 9p21 rs10757274 IntergenicMcPherson et al

TABLE 17 Adjusted association of six SNPs with noncardioembolic strokein VSR Locus Case Control Model 1 Model 2 Genotype n (%) n (%) OR (90%CI) p q OR (90% CI) p C9p21 GG + GA 386 (76.7) 568 (72.4) 1.20(0.95-1.50) 0.10 0.15 1.14 (0.89-1.46) 0.20 GG 139 (27.6) 154 (19.6)1.59 (1.20-2.11) 0.004 1.45 (1.06-1.98) 0.03 GA 247 (49.1) 414 (52.8)1.05 (0.82-1.34) 0.38 1.02 (0.78-1.33) 0.45 AA 117 (23.3) 216 (27.6) refref KIF6 GG + GA 327 (64.8) 475 (60.7) 1.24 (1.01-1.52) 0.05 0.12 1.23(0.98-1.54) 0.07 GG  73 (14.5) 102 (13.0) 1.24 (0.91-1.69) 0.13 1.30(0.93-1.83) 0.10 GA 254 (50.3) 373 (47.7) 1.24 (1.00-1.53) 0.05 1.20(0.95-1.53) 0.10 AA 178 (35.3) 307 (39.3) ref ref MYH15 CC + CT 281(55.6) 390 (49.8) 1.31 (1.07-1.60) 0.01 0.06 1.25 (1.00-1.56) 0.05 CC 56 (11.1) 72 (9.2) 1.50 (1.06-2.11) 0.03 1.19 (0.80-1.75) 0.24 CT 225(44.5) 318 (40.6) 1.27 (1.03-1.56) 0.03 1.26 (1.00-1.59) 0.05 TT 225(44.5) 394 (50.3) ref ref VAMP8 CC + CT 326 (64.4) 483 (61.6) 1.21(0.99-1.49) 0.06 0.12 1.33 (1.06-1.67) 0.02 CC  77 (15.2) 112 (14.3)1.27 (0.93-1.72) 0.10 1.37 (0.98-1.91) 0.06 CT 249 (49.2) 371 (47.3)1.20 (0.96-1.49) 0.09 1.32 (1.04-1.68) 0.03 TT 180 (35.6) 301 (38.4) refref

TABLE 18 p-value OR Lower OR Upper (two- SNP Gene OUTCOME ADJUST? MODEGENOTYPE OR 90% CI 90% CI sided) hCV1116793 ZNF132 ISCHEMIC NO GEN TC0.83 0.69375216 0.992667515 0.0869 hCV1116793 ZNF132 ISCHEMIC NO ADD T0.84 0.724853655 0.974320962 0.053 hCV1116793 ZNF132 ISCHEMIC NO DOM TCor TT 0.819 0.689223622 0.973935207 0.0578 hCV16093418 LOC646377ISCHEMIC NO GEN AA 1.483 0.912916828 2.408756165 0.1815 hCV16093418LOC646377 ISCHEMIC NO ADD A 1.16 0.992191149 1.356678591 0.118hCV16093418 LOC646377 ISCHEMIC NO DOM AG or AA 1.161 0.9680834371.392968387 0.1766 hCV1754669 Chr 9 ISCHEMIC NO GEN AG 0.849 0.6948981441.0380978 0.1806 hCV1754669 Chr 9 ISCHEMIC NO GEN AA 0.704 0.5534380260.894406866 0.016 hCV1754669 Chr 9 ISCHEMIC NO ADD A 0.839 0.7442930030.946031417 0.0161 hCV1754669 Chr 9 ISCHEMIC NO DOM AG or AA 0.8020.663035663 0.970180153 0.0566 hCV1754669 Chr 9 ISCHEMIC NO REC AA 0.7850.643446754 0.957447873 0.0451 hCV25637605 FSTL4 ISCHEMIC NO DOM AG orAA 1.141 0.96474641 1.349440416 0.1959 hCV26505812 Chr 9 ISCHEMIC NO GENGG 1.434 1.126756329 1.825140554 0.0139 hCV26505812 Chr 9 ISCHEMIC NOADD G 1.193 1.057688641 1.345699564 0.0159 hCV26505812 Chr 9 ISCHEMIC NODOM GA or GG 1.175 0.971230942 1.421611376 0.1636 hCV26505812 Chr 9ISCHEMIC NO REC GG 1.362 1.115126666 1.663679973 0.0111 hCV7425232 MYH15ISCHEMIC NO GEN CT 1.207 1.013056501 1.437676114 0.0772 hCV7425232 MYH15ISCHEMIC NO ADD C 1.138 1.002467038 1.290637136 0.0933 hCV7425232 MYH15ISCHEMIC NO DOM CT or CC 1.207 1.022059286 1.424442487 0.0628 hCV1116793ZNF132 ISCHEMIC YES GEN TC 0.703 0.562477582 0.877572242 0.0091hCV1116793 ZNF132 ISCHEMIC YES ADD T 0.75 0.624608329 0.899631989 0.0093hCV1116793 ZNF132 ISCHEMIC YES DOM TC or TT 0.701 0.5656869190.867894166 0.0063 hCV16093418 LOC646377 ISCHEMIC YES GEN AA 1.8661.045328301 3.330322013 0.0766 hCV16093418 LOC646377 ISCHEMIC YES ADD A1.162 0.960599702 1.404663117 0.1948 hCV16093418 LOC646377 ISCHEMIC YESREC AA 1.841 1.034539603 3.275411467 0.0815 hCV1754669 Chr 9 ISCHEMICYES GEN AA 0.76 0.568372651 1.01549685 0.1192 hCV1754669 Chr 9 ISCHEMICYES ADD A 0.87 0.752699651 1.006107576 0.1151 hCV1754669 Chr 9 ISCHEMICYES DOM AG or AA 0.805 0.638680148 1.014657888 0.1232 hCV2091644 VAMP8ISCHEMIC YES GEN CT 1.401 1.120353768 1.751995633 0.0131 hCV2091644VAMP8 ISCHEMIC YES GEN CC 1.38 1.009559907 1.885674346 0.0901 hCV2091644VAMP8 ISCHEMIC YES ADD C 1.221 1.052766014 1.416485778 0.0267 hCV2091644VAMP8 ISCHEMIC YES DOM CT or CC 1.396 1.129256555 1.725713348 0.0096hCV26505812 Chr 9 ISCHEMIC YES GEN GG 1.388 1.036839351 1.8585990410.0645 hCV26505812 Chr 9 ISCHEMIC YES ADD G 1.171 1.0117277371.355459485 0.0756 hCV26505812 Chr 9 ISCHEMIC YES REC GG 1.3981.096801262 1.782473489 0.0232 hCV945276 KRT5 ISCHEMIC YES REC TT 1.2320.957897979 1.585681051 0.1725 hCV1116793 ZNF132 ATHERO NO GEN TC 0.7870.646590569 0.95833488 0.0454 hCV1116793 ZNF132 ATHERO NO ADD T 0.8190.696165402 0.962297139 0.0419 hCV1116793 ZNF132 ATHERO NO DOM TC or TT0.784 0.648664594 0.947280056 0.0344 hCV1754669 Chr 9 ATHERO NO GEN AG0.833 0.670269439 1.034455809 0.165 hCV1754669 Chr 9 ATHERO NO GEN AA0.676 0.520352663 0.878840811 0.014 hCV1754669 Chr 9 ATHERO NO ADD A0.823 0.72208458 0.937642062 0.0141 hCV1754669 Chr 9 ATHERO NO DOM AG orAA 0.782 0.636551788 0.960683278 0.0493 hCV1754669 Chr 9 ATHERO NO RECAA 0.764 0.614147286 0.950963593 0.043 hCV26505812 Chr 9 ATHERO NO GENGG 1.571 1.210420113 2.038944965 0.0044 hCV26505812 Chr 9 ATHERO NO ADDG 1.251 1.097125415 1.426047313 0.005 hCV26505812 Chr 9 ATHERO NO DOM GAor GG 1.218 0.987731875 1.501018684 0.1217 hCV26505812 Chr 9 ATHERO NOREC GG 1.485 1.199236975 1.839906031 0.0024 hCV7425232 MYH15 ATHERO NOGEN CT 1.291 1.06621554 1.562183465 0.028 hCV7425232 MYH15 ATHERO NO GENCC 1.36 0.995974126 1.856019239 0.1044 hCV7425232 MYH15 ATHERO NO ADD C1.209 1.05488262 1.385651602 0.0221 hCV7425232 MYH15 ATHERO NO DOM CT orCC 1.304 1.087542975 1.562799868 0.0161 hCV945276 KRT5 ATHERO NO GEN TT1.226 0.944746161 1.589848931 0.1986 hCV1116793 ZNF132 ATHERO YES GEN TC0.639 0.501790288 0.814951237 0.0024 hCV1116793 ZNF132 ATHERO YES ADD T0.698 0.570892416 0.853128157 0.0032 hCV1116793 ZNF132 ATHERO YES DOM TCor TT 0.64 0.507110931 0.808823546 0.0017 hCV16093418 LOC646377 ATHEROYES GEN AA 1.762 0.928367604 3.34386559 0.1459 hCV16093418 LOC646377ATHERO YES REC AA 1.74 0.920040581 3.292138982 0.1527 hCV1754669 Chr 9ATHERO YES GEN AA 0.765 0.558483335 1.046582925 0.1596 hCV1754669 Chr 9ATHERO YES ADD A 0.874 0.746743893 1.022073084 0.1568 hCV2091644 VAMP8ATHERO YES GEN CT 1.322 1.038739023 1.682015035 0.0569 hCV2091644 VAMP8ATHERO YES GEN CC 1.366 0.976758835 1.910405456 0.126 hCV2091644 VAMP8ATHERO YES ADD C 1.2 1.023536718 1.407388698 0.0592 hCV2091644 VAMP8ATHERO YES DOM CT or CC 1.332 1.06021742 1.673849394 0.0388 hCV26505812Chr 9 ATHERO YES GEN GG 1.449 1.059805605 1.98082713 0.0512 hCV26505812Chr 9 ATHERO YES ADD G 1.201 1.025903307 1.405546929 0.056 hCV26505812Chr 9 ATHERO YES REC GG 1.431 1.106229626 1.851215592 0.022 hCV3054799KIF6 ATHERO YES ADD G 1.156 0.984174559 1.356831226 0.1385 hCV3054799KIF6 ATHERO YES DOM GA or GG 1.226 0.976764207 1.538041725 0.1403hCV323071 PALLD ATHERO YES GEN GA 0.822 0.647104489 1.044405162 0.178hCV7425232 MYH15 ATHERO YES GEN CT 1.263 1.002774843 1.590469093 0.0961hCV7425232 MYH15 ATHERO YES ADD C 1.152 0.973983418 1.361464556 0.1655hCV7425232 MYH15 ATHERO YES DOM CT or CC 1.248 1.002130266 1.5553055170.0966 hCV1116793 ZNF132 EARLY-ONSET NO GEN TC 0.721 0.5552596150.93717945 0.0401 hCV1116793 ZNF132 EARLY-ONSET NO ADD T 0.7420.596550429 0.9231085 0.0246 hCV1116793 ZNF132 EARLY-ONSET NO DOM TC orTT 0.709 0.550475956 0.912444516 0.025 hCV16093418 LOC646377 EARLY-ONSETNO GEN AA 2.279 1.165213696 4.458870577 0.0434 hCV16093418 LOC646377EARLY-ONSET NO REC AA 2.283 1.172006222 4.448126516 0.0417 hCV1754669Chr 9 EARLY-ONSET NO GEN AA 0.638 0.449570543 0.904532087 0.0342hCV1754669 Chr 9 EARLY-ONSET NO ADD A 0.805 0.677020314 0.9570056340.0392 hCV1754669 Chr 9 EARLY-ONSET NO REC AA 0.657 0.4910432840.880225636 0.0181 hCV26505812 Chr 9 EARLY-ONSET NO GEN GG 1.4541.031679957 2.049942 0.0727 hCV26505812 Chr 9 EARLY-ONSET NO ADD G 1.2051.015074491 1.431092302 0.0737 hCV26505812 Chr 9 EARLY-ONSET NO DOM GAor GG 1.257 0.954270123 1.654681429 0.1722 hCV26505812 Chr 9 EARLY-ONSETNO REC GG 1.308 0.984656431 1.736831541 0.1199 hCV3054799 KIF6EARLY-ONSET NO GEN GA 1.256 0.968081501 1.629118384 0.1499 hCV3054799KIF6 EARLY-ONSET NO DOM GA or GG 1.215 0.949308931 1.553982515 0.1942hCV7425232 MYH15 EARLY-ONSET NO GEN CC 1.411 0.92477899 2.153297741 0.18hCV7425232 MYH15 EARLY-ONSET NO ADD C 1.188 0.989106766 1.426969550.1219 hCV7425232 MYH15 EARLY-ONSET NO DOM CT or CC 1.227 0.9644483491.560176569 0.1624 hCV1116793 ZNF132 EARLY-ONSET YES GEN TC 0.5690.383972632 0.843482605 0.0184 hCV1116793 ZNF132 EARLY-ONSET YES GEN TT0.257 0.07724157 0.857115583 0.0635 hCV1116793 ZNF132 EARLY-ONSET YESADD T 0.551 0.390357614 0.77793835 0.0045 hCV1116793 ZNF132 EARLY-ONSETYES DOM TC or TT 0.536 0.36534707 0.78765705 0.0076 hCV1116793 ZNF132EARLY-ONSET YES REC TT 0.312 0.09554036 1.01979997 0.1057 hCV1754669 Chr9 EARLY-ONSET YES GEN AA 0.531 0.310682745 0.90627091 0.0515 hCV1754669Chr 9 EARLY-ONSET YES ADD A 0.754 0.582569376 0.975219212 0.071hCV1754669 Chr 9 EARLY-ONSET YES REC AA 0.471 0.300175493 0.7403649790.0061 hCV26505812 Chr 9 EARLY-ONSET YES GEN GA 1.613 1.0360956852.50964297 0.0756 hCV26505812 Chr 9 EARLY-ONSET YES GEN GG 1.6070.955315621 2.704490393 0.1335 hCV26505812 Chr 9 EARLY-ONSET YES ADD G1.267 0.980473167 1.638072097 0.129 hCV26505812 Chr 9 EARLY-ONSET YESDOM GA or GG 1.611 1.056911526 2.455300114 0.0627 hCV3054799 KIF6EARLY-ONSET YES GEN GA 1.469 0.997042382 2.16444072 0.1027 hCV3054799KIF6 EARLY-ONSET YES DOM GA or GG 1.423 0.980591812 2.063903309 0.1192hCV323071 PALLD EARLY-ONSET YES GEN GA 0.722 0.490060464 1.0642033590.1673 hCV323071 PALLD EARLY-ONSET YES DOM GA or GG 0.74 0.5154543681.061949638 0.1704

TABLE 19A Ref ALL Case Case Control Study Marker Gene rs Allele Allelecnt ALL frq cnt frq cnt UCSF hCV1053082  NEU3 rs544115  C T 884 0.2039216 0.1898 668 CCF VSR hCV1053082  NEU3 rs544115  C T 500 0.1836 1770.1615 323 UCSF hCV1116757  rs3794971  T C 844 0.1946 206 0.181 638 CCFVSR hCV1116757  rs3794971  T C 454 0.1695 164 0.1513 290 UCSFhCV11425801 PEX6 rs3805953  T C 2068 0.4763 570 0.5009 1498 CCF VSRhCV11425801 PEX6 rs3805953  T C 1320 0.4857 554 0.5064 766 UCSFhCV11425842 GNMT rs10948059 C T 2048 0.4723 513 0.4516 1535 CCF VSRhCV11425842 GNMT rs10948059 C T 1258 0.4618 485 0.4425 773 UCSFhCV11548152 rs11580249 G T 707 0.1631 210 0.1845 497 CCF VSR hCV11548152rs11580249 G T 413 0.1513 184 0.1673 229 UCSF hCV11738775 rs6754561  T C1616 0.3725 394 0.3462 1222 CCF VSR hCV11738775 rs6754561  T C 10250.3766 387 0.3531 638 UCSF hCV11758801 GUCY1B2 rs11841997 C G 131 0.030244 0.0387 87 CCF VSR hCV11758801 GUCY1B2 rs11841997 C G 87 0.0319 440.04 43 UCSF hCV11861255 GRIK3 rs529407  A G 1038 0.2392 260 0.2285 778CCF VSR hCV11861255 GRIK3 rs529407  A G 674 0.2506 245 0.226 429 UCSFhCV12071939 rs1950943  G T 929 0.2142 221 0.1942 708 CCF VSR hCV12071939rs1950943  G T 532 0.1952 193 0.1755 339 UCSF hCV1209800  CLIC5rs35067690 G T 207 0.0477 38 0.0335 169 CCF VSR hCV1209800  CLIC5rs35067690 G T 111 0.0406 34 0.0309 77 UCSF hCV1262973  PLEKHG3rs229653  G A 382 0.088 114 0.1002 268 CCF VSR hCV1262973  PLEKHG3rs229653  G A 277 0.1024 127 0.118 150 UCSF hCV1348610  C9orf46rs3739636  G A 2013 0.4645 559 0.4921 1454 CCF VSR hCV1348610  C9orf46rs3739636  G A 1223 0.4567 512 0.4794 711 UCSF hCV1408483  BCL2rs17070848 C T 719 0.1657 209 0.1837 510 CCF VSR hCV1408483  BCL2rs17070848 C T 526 0.1931 232 0.2117 294 UCSF hCV1452085  TRIM22rs12223005 C A 468 0.1078 111 0.0975 357 CCF VSR hCV1452085  TRIM22rs12223005 C A 279 0.1021 98 0.0889 181 UCSF hCV15851766 APC rs2229995 G A 87 0.0201 14 0.0123 73 CCF VSR hCV15851766 APC rs2229995  G A 590.022 15 0.0139 44 UCSF hCV15857769 rs2924914  C T 1314 0.3029 3680.3234 946 CCF VSR hCV15857769 rs2924914  C T 786 0.2883 331 0.3015 455UCSF hCV15879601 C6orf142 rs2275769  C T 333 0.0767 70 0.0615 263 CCFVSR hCV15879601 C6orf142 rs2275769  C T 171 0.0628 59 0.0537 112 UCSFhCV16134786 rs2857595  G A 774 0.1785 226 0.1989 548 CCF VSR hCV16134786rs2857595  G A 510 0.1868 227 0.2064 283 UCSF hCV1619596  FKBP1Ars1048621  G A 1198 0.2764 337 0.2961 861 CCF VSR hCV1619596  FKBP1Ars1048621  G A 675 0.2474 297 0.27 378 UCSF hCV16336   HD rs362277  C T469 0.108 107 0.094 362 CCF VSR hCV16336   HD rs362277  C T 294 0.107997 0.0885 197 UCSF hCV1723718  UMODL1 rs12481805 G A 1336 0.3081 3770.3313 959 CCF VSR hCV1723718  UMODL1 rs12481805 G A 779 0.2858 3360.306 443 UCSF hCV1958451  MIER1 rs2985822  G T 1073 0.2475 256 0.225817 CCF VSR hCV1958451  MIER1 rs2985822  G T 676 0.2487 248 0.2271 428UCSF hCV2121658  rs1187332  G A 534 0.1232 120 0.1058 414 CCF VSRhCV2121658  rs1187332  G A 331 0.1226 119 0.1104 212 UCSF hCV2358247 SPINT4 rs415989  A G 290 0.0669 88 0.0775 202 CCF VSR hCV2358247  SPINT4rs415989  A G 150 0.0549 77 0.0699 73 UCSF hCV2390937  LOC441108rs739719  C A 318 0.0733 70 0.0615 248 CCF VSR hCV2390937  LOC441108rs739719  C A 185 0.0678 60 0.0545 125 UCSF hCV25473186 NPY2R rs2880415 T C 2044 0.4708 566 0.4974 1478 CCF VSR hCV25473186 NPY2R rs2880415  T C1181 0.4336 509 0.4653 672 UCSF hCV25596936 EPHA1 rs6967117  C T 3080.0709 92 0.0808 216 CCF VSR hCV25596936 EPHA1 rs6967117  C T 241 0.0884118 0.1073 123 UCSF hCV25615822 DHODH NONE C T 114 0.0263 35 0.0308 79CCF VSR hCV25615822 DHODH NONE C T 113 0.0414 56 0.0508 57 UCSFhCV25983294 EDG2 rs3739709  G A 821 0.1892 190 0.1673 631 CCF VSRhCV25983294 EDG2 rs3739709  G A 541 0.1988 197 0.1794 344 UCSFhCV2637554  CHPT1 rs3205421  T C 1293 0.2985 368 0.3245 925 CCF VSRhCV2637554  CHPT1 rs3205421  T C 842 0.3109 363 0.3336 479 UCSFhCV26478797 CHSY-2 rs2015018  G A 1100 0.2537 266 0.2337 834 CCF VSRhCV26478797 CHSY-2 rs2015018  G A 721 0.2653 270 0.2473 451 UCSFhCV26881276 C11orf47 rs2344829  A G 1429 0.3297 392 0.3451 1037 CCF VSRhCV26881276 C11orf47 rs2344829  A G 963 0.3527 418 0.38 545 UCSFhCV27077072 rs8060368  C T 1429 0.3293 353 0.3102 1076 CCF VSRhCV27077072 rs8060368  C T 911 0.3339 346 0.3145 565 UCSF hCV27473671C9orf4 rs3750465  T C 1270 0.2925 357 0.3137 913 CCF VSR hCV27473671C9orf4 rs3750465  T C 738 0.2709 324 0.2945 414 UCSF hCV27494483SLC22A15 rs3748743  C T 226 0.0521 72 0.0633 154 CCF VSR hCV27494483SLC22A15 rs3748743  C T 127 0.0466 63 0.0573 64 UCSF hCV27504565 MUTYHrs3219489  C G 1135 0.2618 277 0.2434 858 CCF VSR hCV27504565 MUTYHrs3219489  C G 594 0.2174 213 0.1933 381 UCSF hCV27511436 FZD1rs3750145  T C 687 0.1592 157 0.1389 530 CCF VSR hCV27511436 FZD1rs3750145  T C 474 0.1736 173 0.1573 301 UCSF hCV2769503  rs4787956  A G1495 0.3445 426 0.3743 1069 CCF VSR hCV2769503  rs4787956  A G 8910.3317 393 0.3666 498 UCSF hCV27892569 NRXN3 rs4903741  T C 1022 0.2364289 0.2544 733 CCF VSR hCV27892569 NRXN3 rs4903741  T C 626 0.23 2680.2432 358 UCSF hCV28036404 RBL1 rs4812768  T A 875 0.2017 216 0.1905659 CCF VSR hCV28036404 RBL1 rs4812768  T A 511 0.1879 182 0.1667 329UCSF hCV2851380  rs12445805 G C 450 0.1037 99 0.0871 351 CCF VSRhCV2851380  rs12445805 G C 320 0.1173 113 0.1027 207 UCSF hCV29401764LOC646588 rs7793552  C T 1402 0.3233 347 0.3049 1055 CCF VSR hCV29401764LOC646588 rs7793552  C T 913 0.3357 337 0.3086 576 UCSF hCV29537898rs6073804  C T 393 0.0907 120 0.1056 273 CCF VSR hCV29537898 rs6073804 C T 216 0.0796 100 0.0921 116 UCSF hCV29539757 KCNQ3 rs10110659 C A 13110.3022 312 0.2746 999 CCF VSR hCV29539757 KCNQ3 rs10110659 C A 8700.3191 318 0.2896 552 UCSF hCV302629  UBAC2 rs9284183  A G 1247 0.2876359 0.316 888 CCF VSR hCV302629  UBAC2 rs9284183  A G 763 0.2815 3190.2932 444 UCSF hCV30308202 LAMA2 rs9482985  G C 917 0.2115 219 0.1924698 CCF VSR hCV30308202 LAMA2 rs9482985  G C 549 0.2017 200 0.1828 349UCSF hCV3054550  AIG1 rs1559599  C T 641 0.1476 189 0.1661 452 CCF VSRhCV3054550  AIG1 rs1559599  C T 434 0.1589 189 0.1715 245 UCSFhCV3082219  RFXDC1 rs1884833  G A 505 0.1164 148 0.1301 357 CCF VSRhCV3082219  RFXDC1 rs1884833  G A 344 0.127 159 0.147 185 UCSFhCV31137507 CLOCK rs7660668  G C 1165 0.2683 328 0.2882 837 CCF VSRhCV31137507 CLOCK rs7660668  G C 741 0.272 317 0.2892 424 UCSFhCV31227848 HIVEP3 rs11809423 C T 172 0.0396 61 0.0536 111 CCF VSRhCV31227848 HIVEP3 rs11809423 C T 120 0.044 64 0.0583 56 UCSFhCV31573621 SKAP1 rs11079818 T C 1223 0.2817 295 0.2592 928 CCF VSRhCV31573621 SKAP1 rs11079818 T C 739 0.2751 276 0.2575 463 UCSFhCV31705214 LOC645397 rs12804599 A T 984 0.2266 283 0.2487 701 CCF VSRhCV31705214 LOC645397 rs12804599 A T 596 0.2183 266 0.2418 330 UCSFhCV32160712 rs11079160 A T 743 0.1713 221 0.1942 522 CCF VSR hCV32160712rs11079160 A T 432 0.1595 191 0.1752 241 UCSF hCV435733  rs10276935 C G1346 0.3103 383 0.3366 963 CCF VSR hCV435733  rs10276935 C G 819 0.3004345 0.3142 474 UCSF hCV454333  NVL rs10916581 C T 590 0.136 139 0.1224451 CCF VSR hCV454333  NVL rs10916581 C T 324 0.1194 110 0.0998 214 UCSFhCV540056  SPHK1 rs346802  C T 163 0.0376 32 0.0281 131 CCF VSRhCV540056  SPHK1 rs346802  C T 90 0.033 26 0.0237 64 UCSF hCV7917138 OR5H8P rs9822460  A G 860 0.1984 255 0.2241 605 CCF VSR hCV7917138 OR5H8P rs9822460  A G 538 0.1981 231 0.2115 307 UCSF hCV8147903 FLJ25715 rs680014  G A 971 0.2237 225 0.1977 746 CCF VSR hCV8147903 FLJ25715 rs680014  G A 577 0.2124 214 0.1963 363 UCSF hCV8754449  TESK2rs781226  C T 1126 0.2596 277 0.2434 849 CCF VSR hCV8754449  TESK2rs781226  C T 606 0.2226 218 0.1989 388 UCSF hCV8820007  rs938390  T A1055 0.2432 265 0.2333 790 CCF VSR hCV8820007  rs938390  T A 651 0.2399234 0.2135 417 UCSF hCV8942032  DDR1 rs1264352  G C 610 0.1406 1790.1573 431 CCF VSR hCV8942032  DDR1 rs1264352  G C 366 0.1343 165 0.1505201 Control ALL ALL Case Case Control Control Study Marker frq Allelecnt frq cnt frq cnt frq UCSF hCV1053082  0.2089 C 3452 0.796 922 0.81022530 0.7911 CCF VSR hCV1053082  0.1984 C 2224 0.816 919 0.8385 13050.8016 UCSF hCV1116757  0.1994 T 3494 0.805 932 0.819 2562 0.8006 CCFVSR hCV1116757  0.1819 T 2224 0.831 920 0.8487 1304 0.8181 UCSFhCV11425801 0.4675 T 2274 0.524 568 0.4991 1706 0.5325 CCF VSRhCV11425801 0.4717 T 1398 0.514 540 0.4936 858 0.5283 UCSF hCV114258420.4797 C 2288 0.528 623 0.5484 1665 0.5203 CCF VSR hCV11425842 0.4748 C1466 0.538 611 0.5575 855 0.5252 UCSF hCV11548152 0.1555 G 3627 0.837928 0.8155 2699 0.8445 CCF VSR hCV11548152 0.1405 G 2317 0.849 9160.8327 1401 0.8595 UCSF hCV11738775 0.3819 T 2722 0.628 744 0.6538 19780.6181 CCF VSR hCV11738775 0.3924 T 1697 0.623 709 0.6469 988 0.6076UCSF hCV11758801 0.0272 C 4207 0.97 1092 0.9613 3115 0.9728 CCF VSRhCV11758801 0.0264 C 2643 0.968 1056 0.96 1587 0.9736 UCSF hCV118612550.243 A 3302 0.761 878 0.7715 2424 0.757 CCF VSR hCV11861255 0.2671 A2016 0.749 839 0.774 1177 0.7329 UCSF hCV12071939 0.2212 G 3409 0.786917 0.8058 2492 0.7788 CCF VSR hCV12071939 0.2085 G 2194 0.805 9070.8245 1287 0.7915 UCSF hCV1209800  0.0527 G 4133 0.952 1098 0.9665 30350.9473 CCF VSR hCV1209800  0.0472 G 2621 0.959 1068 0.9691 1553 0.9528UCSF hCV1262973  0.0837 G 3958 0.912 1024 0.8998 2934 0.9163 CCF VSRhCV1262973  0.0921 G 2427 0.898 949 0.882 1478 0.9079 UCSF hCV1348610 0.4547 G 2321 0.536 577 0.5079 1744 0.5453 CCF VSR hCV1348610  0.4416 G1455 0.543 556 0.5206 899 0.5584 UCSF hCV1408483  0.1594 C 3619 0.834929 0.8163 2690 0.8406 CCF VSR hCV1408483  0.1806 C 2198 0.807 8640.7883 1334 0.8194 UCSF hCV1452085  0.1115 C 3872 0.892 1027 0.9025 28450.8885 CCF VSR hCV1452085  0.111 C 2453 0.898 1004 0.9111 1449 0.889UCSF hCV15851766 0.0228 G 4245 0.98 1122 0.9877 3123 0.9772 CCF VSRhCV15851766 0.0274 G 2621 0.978 1061 0.9861 1560 0.9726 UCSF hCV158577690.2956 C 3024 0.697 770 0.6766 2254 0.7044 CCF VSR hCV15857769 0.2795 C1940 0.712 767 0.6985 1173 0.7205 UCSF hCV15879601 0.0821 C 4009 0.9231068 0.9385 2941 0.9179 CCF VSR hCV15879601 0.0689 C 2553 0.937 10390.9463 1514 0.9311 UCSF hCV16134786 0.1712 G 3562 0.822 910 0.8011 26520.8288 CCF VSR hCV16134786 0.1736 G 2220 0.813 873 0.7936 1347 0.8264UCSF hCV1619596  0.2694 G 3136 0.724 801 0.7039 2335 0.7306 CCF VSRhCV1619596  0.2322 G 2053 0.753 803 0.73 1250 0.7678 UCSF hCV16336  0.113 C 3873 0.892 1031 0.906 2842 0.887 CCF VSR hCV16336   0.121 C 24300.892 999 0.9115 1431 0.879 UCSF hCV1723718  0.2999 G 3000 0.692 7610.6687 2239 0.7001 CCF VSR hCV1723718  0.2721 G 1947 0.714 762 0.6941185 0.7279 UCSF hCV1958451  0.2555 G 3263 0.753 882 0.775 2381 0.7445CCF VSR hCV1958451  0.2632 G 2042 0.751 844 0.7729 1198 0.7368 UCSFhCV2121658  0.1294 G 3800 0.877 1014 0.8942 2786 0.8706 CCF VSRhCV2121658  0.1307 G 2369 0.877 959 0.8896 1410 0.8693 UCSF hCV2358247 0.0631 A 4046 0.933 1048 0.9225 2998 0.9369 CCF VSR hCV2358247  0.0448 A2582 0.945 1025 0.9301 1557 0.9552 UCSF hCV2390937  0.0775 C 4022 0.9271068 0.9385 2954 0.9225 CCF VSR hCV2390937  0.0767 C 2545 0.932 10400.9455 1505 0.9233 UCSF hCV25473186 0.4613 T 2298 0.529 572 0.5026 17260.5387 CCF VSR hCV25473186 0.4123 T 1543 0.566 585 0.5347 958 0.5877UCSF hCV25596936 0.0674 C 4034 0.929 1046 0.9192 2988 0.9326 CCF VSRhCV25596936 0.0756 C 2485 0.912 982 0.8927 1503 0.9244 UCSF hCV256158220.0247 C 4224 0.974 1101 0.9692 3123 0.9753 CCF VSR hCV25615822 0.035 C2617 0.959 1046 0.9492 1571 0.965 UCSF hCV25983294 0.1969 G 3519 0.811946 0.8327 2573 0.8031 CCF VSR hCV25983294 0.2118 G 2181 0.801 9010.8206 1280 0.7882 UCSF hCV2637554  0.2892 T 3039 0.702 766 0.6755 22730.7108 CCF VSR hCV2637554  0.2957 T 1866 0.689 725 0.6664 1141 0.7043UCSF hCV26478797 0.2608 G 3236 0.746 872 0.7663 2364 0.7392 CCF VSRhCV26478797 0.2774 G 1997 0.735 822 0.7527 1175 0.7226 UCSF hCV268812760.3243 A 2905 0.67 744 0.6549 2161 0.6757 CCF VSR hCV26881276 0.3344 A1767 0.647 682 0.62 1085 0.6656 UCSF hCV27077072 0.336 C 2911 0.671 7850.6898 2126 0.664 CCF VSR hCV27077072 0.3471 C 1817 0.666 754 0.68551063 0.6529 UCSF hCV27473671 0.285 T 3072 0.708 781 0.6863 2291 0.715CCF VSR hCV27473671 0.2549 T 1986 0.729 776 0.7055 1210 0.7451 UCSFhCV27494483 0.0481 C 4114 0.948 1066 0.9367 3048 0.9519 CCF VSRhCV27494483 0.0394 C 2599 0.953 1037 0.9427 1562 0.9606 UCSF hCV275045650.2683 C 3201 0.738 861 0.7566 2340 0.7317 CCF VSR hCV27504565 0.2337 C2138 0.783 889 0.8067 1249 0.7663 UCSF hCV27511436 0.1665 T 3627 0.841973 0.8611 2654 0.8335 CCF VSR hCV27511436 0.1847 T 2256 0.826 9270.8427 1329 0.8153 UCSF hCV2769503  0.3339 A 2845 0.656 712 0.6257 21330.6661 CCF VSR hCV2769503  0.3086 A 1795 0.668 679 0.6334 1116 0.6914UCSF hCV27892569 0.2299 T 3302 0.764 847 0.7456 2455 0.7701 CCF VSRhCV27892569 0.221 T 2096 0.77 834 0.7568 1262 0.779 UCSF hCV280364040.2057 T 3463 0.798 918 0.8095 2545 0.7943 CCF VSR hCV28036404 0.2021 T2209 0.812 910 0.8333 1299 0.7979 UCSF hCV2851380  0.1096 G 3890 0.8961037 0.9129 2853 0.8904 CCF VSR hCV2851380  0.1271 G 2408 0.883 9870.8973 1421 0.8729 UCSF hCV29401764 0.3299 C 2934 0.677 791 0.6951 21430.6701 CCF VSR hCV29401764 0.3538 C 1807 0.664 755 0.6914 1052 0.6462UCSF hCV29537898 0.0854 C 3941 0.909 1016 0.8944 2925 0.9146 CCF VSRhCV29537898 0.0713 C 2496 0.92 986 0.9079 1510 0.9287 UCSF hCV295397570.312 C 3027 0.698 824 0.7254 2203 0.688 CCF VSR hCV29539757 0.3391 C1856 0.681 780 0.7104 1076 0.6609 UCSF hCV302629  0.2775 A 3089 0.712777 0.684 2312 0.7225 CCF VSR hCV302629  0.2737 A 1947 0.719 769 0.70681178 0.7263 UCSF hCV30308202 0.2183 G 3419 0.789 919 0.8076 2500 0.7817CCF VSR hCV30308202 0.2144 G 2173 0.798 894 0.8172 1279 0.7856 UCSFhCV3054550  0.1411 C 3701 0.852 949 0.8339 2752 0.8589 CCF VSRhCV3054550  0.1503 C 2298 0.841 913 0.8285 1385 0.8497 UCSF hCV3082219 0.1115 G 3835 0.884 990 0.8699 2845 0.8885 CCF VSR hCV3082219  0.1138 G2364 0.873 923 0.853 1441 0.8862 UCSF hCV31137507 0.2612 G 3177 0.732810 0.7118 2367 0.7388 CCF VSR hCV31137507 0.2604 G 1983 0.728 7790.7108 1204 0.7396 UCSF hCV31227848 0.0347 C 4168 0.96 1077 0.9464 30910.9653 CCF VSR hCV31227848 0.0344 C 2608 0.956 1034 0.9417 1574 0.9656UCSF hCV31573621 0.2896 T 3119 0.718 843 0.7408 2276 0.7104 CCF VSRhCV31573621 0.2869 T 1947 0.725 796 0.7425 1151 0.7131 UCSF hCV317052140.2188 A 3358 0.773 855 0.7513 2503 0.7812 CCF VSR hCV31705214 0.2025 A2134 0.782 834 0.7582 1300 0.7975 UCSF hCV32160712 0.1631 A 3595 0.829917 0.8058 2678 0.8369 CCF VSR hCV32160712 0.1489 A 2276 0.841 8990.8248 1377 0.8511 UCSF hCV435733  0.3009 C 2992 0.69 755 0.6634 22370.6991 CCF VSR hCV435733  0.2912 C 1907 0.7 753 0.6858 1154 0.7088 UCSFhCV454333  0.1408 C 3748 0.864 997 0.8776 2751 0.8592 CCF VSR hCV454333 0.1328 C 2390 0.881 992 0.9002 1398 0.8672 UCSF hCV540056  0.0409 C 41770.962 1106 0.9719 3071 0.9591 CCF VSR hCV540056  0.0394 C 2634 0.9671072 0.9763 1562 0.9606 UCSF hCV7917138  0.1893 A 3474 0.802 883 0.77592591 0.8107 CCF VSR hCV7917138  0.189 A 2178 0.802 861 0.7885 1317 0.811UCSF hCV8147903  0.233 G 3369 0.776 913 0.8023 2456 0.767 CCF VSRhCV8147903  0.2232 G 2139 0.788 876 0.8037 1263 0.7768 UCSF hCV8754449 0.2653 C 3212 0.74 861 0.7566 2351 0.7347 CCF VSR hCV8754449  0.2386 C2116 0.777 878 0.8011 1238 0.7614 UCSF hCV8820007  0.2467 T 3283 0.757871 0.7667 2412 0.7533 CCF VSR hCV8820007  0.2577 T 2063 0.76 862 0.78651201 0.7423 UCSF hCV8942032  0.1347 G 3728 0.859 959 0.8427 2769 0.8653CCF VSR hCV8942032  0.1233 G 2360 0.866 931 0.8495 1429 0.8767

TABLE 19B ALL ALL Case Case Control Control ALL Study Marker rs Genotcnt frq cnt frq cnt frq Genot cnt ALL frq UCSFCCF hCV1053082  rs544115 T T 98 0.0452 17 0.0299 81 0.0507 T C 688 0.3173 VSR hCV1053082 rs544115  T T 52 0.0382 16 0.0292 36 0.0442 T C 396 0.2907 UCSFCCFhCV1116757  rs3794971  C C 85 0.0392 24 0.0422 61 0.0381 C T 674 0.3107VSR hCV1116757  rs3794971  C C 41 0.0306 13 0.024 28 0.0351 C T 3720.2778 UCSFCCF hCV11425801 rs3805953  C C 499 0.2298 143 0.2513 3560.2222 C T 1070 0.4929 VSR hCV11425801 rs3805953  C C 319 0.2347 1400.2559 179 0.2204 C T 682 0.5018 UCSFCCF hCV11425842 rs10948059 T T 4860.2242 111 0.1954 375 0.2344 T C 1076 0.4963 VSR hCV11425842 rs10948059T T 283 0.2078 104 0.1898 179 0.2199 T C 692 0.5081 UCSFCCF hCV11548152rs11580249 T T 52 0.024 15 0.0264 37 0.0232 T G 603 0.2783 VSRhCV11548152 rs11580249 T T 34 0.0249 17 0.0309 17 0.0209 T G 345 0.2527UCSFCCF hCV11738775 rs6754561  C C 279 0.1286 57 0.1002 222 0.1388 C T1058 0.4878 VSR hCV11738775 rs6754561  C C 201 0.1477 65 0.1186 1360.1673 C T 623 0.4578 UCSFCCF hCV11758801 rs11841997 G G 4 0.0018 20.0035 2 0.0012 G C 123 0.0567 VSR hCV11758801 rs11841997 G G 2 0.0015 20.0036 0 0 G C 83 0.0608 UCSFCCF hCV11861255 rs529407  G G 144 0.0664 270.0475 117 0.0731 G A 750 0.3456 VSR hCV11861255 rs529407  G G 95 0.070630 0.0554 65 0.0809 G A 484 0.3599 UCSFCCF hCV12071939 rs1950943  T T 940.0433 15 0.0264 79 0.0494 T G 741 0.3416 VSR hCV12071939 rs1950943  T T61 0.0448 25 0.0455 36 0.0443 T G 410 0.3008 UCSFCCF hCV1209800 rs35067690 T T 4 0.0018 0 0 4 0.0025 T G 199 0.0917 VSR hCV1209800 rs35067690 T T 4 0.0029 0 0 4 0.0049 T G 103 0.0754 UCSFCCF hCV1262973 rs229653  A A 29 0.0134 11 0.0193 18 0.0112 A G 324 0.1493 VSRhCV1262973  rs229653  A A 16 0.0118 5 0.0093 11 0.0135 A G 245 0.1812UCSFCCF hCV1348610  rs3739636  A A 474 0.2187 135 0.2377 339 0.212 A G1065 0.4912 VSR hCV1348610  rs3739636  A A 301 0.2566 137 0.2566 1640.2037 A G 621 0.4638 UCSFCCF hCV1408483  rs17070848 T T 56 0.0246 140.0246 42 0.0262 T C 607 0.2799 VSR hCV1408483  rs17070848 T T 50 0.040122 0.0401 28 0.0344 T C 426 0.3128 UCSFCCF hCV1452085  rs12223005 A A 280.0053 3 0.0053 25 0.0156 A C 412 0.1899 VSR hCV1452085  rs12223005 A A17 0.0127 7 0.0127 10 0.0123 A C 245 0.1794 UCSFCCF hCV15851766rs2229995  A A 0 0 0 0 0 0 A G 87 0.0402 VSR hCV15851766 rs2229995  A A0 0 0 0 0 0 A G 59 0.044 UCSFCCF hCV15857769 rs2924914  T T 212 0.097765 0.1142 147 0.0919 T C 890 0.4183 VSR hCV15857769 rs2924914  T T 1060.0778 53 0.0965 53 0.0651 T C 574 0.4098 UCSFCCF hCV15879601 rs2275769 T T 13 0.006 2 0.0035 11 0.0069 T C 307 0.116 VSR hCV15879601 rs2275769 T T 8 0.0059 0 0 8 0.0098 T C 155 0.1075 UCSFCCF hCV16134786 rs2857595 A A 72 0.0332 22 0.0387 50 0.0312 A G 630 0.3204 VSR hCV16134786rs2857595  A A 53 0.0388 22 0.04 31 0.038 A G 404 0.3327 UCSFCCFhCV1619596  rs1048621  A A 186 0.0858 54 0.0949 132 0.0826 A G 8260.4025 VSR hCV1619596  rs1048621  A A 83 0.0609 37 0.0673 46 0.0565 A G509 0.4055 UCSFCCF hCV16336   rs362277  T T 31 0.0143 7 0.0123 24 0.015T C 407 0.1634 VSR hCV16336   rs362277  T T 15 0.011 2 0.0036 13 0.016 TC 264 0.1697 UCSFCCF hCV1723718  rs12481805 A A 199 0.0918 61 0.1072 1380.0863 A G 938 0.4482 VSR hCV1723718  rs12481805 A A 123 0.0902 530.0965 70 0.086 A G 533 0.4189 UCSFCCF hCV1958451  rs2985822  T T 1350.623 30 0.0527 105 0.0657 T G 803 0.3445 VSR hCV1958451  rs2985822  T T90 0.0662 27 0.0495 63 0.0775 T G 496 0.3553 UCSFCCF hCV2121658 rs1187332  A A 23 0.0106 6 0.0106 17 0.0106 A G 488 0.1905 VSRhCV2121658  rs1187332  A A 18 0.0133 3 0.0056 15 0.0185 A G 295 0.2096UCSFCCF hCV2358247  rs415989  G G 14 0.0065 2 0.0035 12 0.0075 G A 2620.1208 VSR hCV2358247  rs415989  G G 5 0.0037 5 0.0091 0 0 G A 1400.1025 UCSFCCF hCV2390937  rs739719  A A 12 0.0055 2 0.0035 10 0.0062 AC 294 0.1355 VSR hCV2390937  rs739719  A A 3 0.0022 1 0.0018 2 0.0025 AC 179 0.1311 UCSFCCF hCV25473186 rs2880415  C C 488 0.2248 135 0.2373353 0.2203 C T 1068 0.4919 VSR hCV25473186 rs2880415  C C 246 0.1806 1090.1993 137 0.1681 C T 689 0.5059 UCSFCCF hCV25596936 rs6967117  T T 130.006 2 0.0035 11 0.0069 T C 282 0.1299 VSR hCV25596936 rs6967117  T T15 0.011 7 0.0127 8 0.0098 T C 211 0.1548 UCSFCCF hCV25615822 NONE T T 10.0005 1 0.0018 0 0 T C 112 0.0516 VSR hCV25615822 NONE T T 2 0.0015 10.0018 1 0.0012 T C 109 0.0799 UCSFCCF hCV25983294 rs3739709  A A 750.0346 19 0.0335 56 0.035 A G 671 0.3092 VSR hCV25983294 rs3739709  A A64 0.047 23 0.0419 41 0.0505 A G 413 0.3035 UCSFCCF hCV2637554 rs3205421  C C 190 0.0877 64 0.1129 126 0.0788 C T 913 0.4215 VSRhCV2637554  rs3205421  C C 139 0.1027 63 0.1158 76 0.0938 C T 564 0.4165UCSFCCF hCV26478797 rs2015018  A A 122 0.0563 31 0.0545 91 0.0569 A G856 0.3948 VSR hCV26478797 rs2015018  A A 95 0.0699 28 0.0513 67 0.0824A G 531 0.3907 UCSFCCF hCV26881276 rs2344829  G G 250 0.1154 66 0.1162184 0.1151 G A 929 0.4287 VSR hCV26881276 rs2344829  G G 183 0.1341 860.1564 97 0.119 G A 597 0.4374 UCSFCCF hCV27077072 rs8060368  T T 2370.1092 60 0.1054 177 0.1106 T C 955 0.4401 VSR hCV27077072 rs8060368  TT 152 0.1114 54 0.0982 98 0.1204 T C 607 0.445 UCSFCCF hCV27473671rs3750465  C C 183 0.0843 54 0.0949 129 0.0805 C T 904 0.4164 VSRhCV27473671 rs3750465  C C 103 0.0756 51 0.0927 52 0.064 C T 532 0.3906UCSFCCF hCV27494483 rs3748742  T T 12 0.005 4 0.007 8 0.005 T C 2020.0931 VSR hCV27494483 rs3748742  T T 3 0.0022 2 0.0036 1 0.0012 T C 1210.0888 UCSFCCF hCV27504565 rs3219489  G G 138 0.0637 39 0.0685 99 0.0619G C 859 0.3962 VSR hCV27504565 rs3219489  G G 67 0.049 13 0.0236 540.0663 G C 460 0.3367 UCSFCCF hCV27511436 rs3750145  C C 55 0.0255 50.0088 50 0.0314 C T 577 0.2375 VSR hCV27511436 rs3750145  C C 47 0.034416 0.0291 31 0.038 C T 380 0.2784 UCSFCCF hCV2769503  rs4787956  G G 2530.1166 74 0.1301 179 0.1118 G A 989 0.4558 VSR hCV2769503  rs4787956  GG 146 0.1087 65 0.1213 81 0.1004 G A 599 0.446 UCSFCCF hCV27892569rs4903741  C C 113 0.0523 35 0.0616 78 0.0489 C T 796 0.3682 VSRhCV27892569 rs4903741  C C 88 0.0647 34 0.0617 54 0.0667 C T 450 0.3306UCSFCCF hCV28036404 rs4812768  A A 99 0.0456 17 0.03 82 0.0512 A T 6770.3121 VSR hCV28036404 rs4812768  A A 39 0.0287 13 0.0238 26 0.0319 A T433 0.3184 UCSFCCF hCV2851380  rs12445805 C C 32 0.0147 4 0.007 280.0175 C G 386 0.1779 VSR hCV2851380  rs12445805 C C 21 0.0154 7 0.012714 0.0172 C G 278 0.2038 UCSFCCF hCV29401764 rs7793552  T T 223 0.102962 0.109 161 0.1007 T C 956 0.441 VSR hCV29401764 rs7793552  T T 1590.1169 58 0.1062 101 0.1241 T C 595 0.4375 UCSFCCF hCV29537898rs6073804  T T 23 0.0106 10 0.0176 13 0.0081 T C 347 0.1601 VSRhCV29537898 rs6073804  T T 6 0.0044 5 0.0092 1 0.0012 T C 204 0.1504UCSFCCF hCV29538757 rs10110659 A A 192 0.0885 49 0.0863 143 0.0893 A C927 0.4274 VSR hCV29538757 rs10110659 A A 136 0.0998 46 0.0838 90 0.1106A C 598 0.4387 UCSFCCF hCV302629  rs9284183  G G 185 0.0853 68 0.1197117 0.0731 G A 877 0.4045 VSR hCV302629  rs9284183  G G 111 0.0819 550.1011 56 0.0691 G A 541 0.3993 UCSFCCF hCV30308202 rs9482985  C C 1010.0466 17 0.0299 84 0.0525 C G 715 0.3298 VSR hCV30308202 rs9482985  C C66 0.0485 25 0.0457 41 0.0504 C G 417 0.3064 UCSFCCF hCV3054550 rs1559599  T T 50 0.023 17 0.0299 33 0.0206 T C 541 0.2492 VSRhCV3054550  rs1559599  T T 36 0.0264 14 0.0254 22 0.027 T C 362 0.265UCSFCCF hCV3082219  rs1884833  A A 27 0.0124 7 0.0123 20 0.0125 A G 4510.2078 VSR hCV3082219  rs1884833  A A 21 0.0155 11 0.0203 10 0.0123 A G302 0.223 UCSFCCF hCV31137507 rs7660668  C C 162 0.0746 47 0.0826 1150.0718 C G 841 0.3874 VSR hCV31137507 rs7660668  C C 101 0.0742 460.0839 55 0.0676 C G 539 0.3957 UCSFCCF hCV31227848 rs11809423 T T 40.0018 1 0.0018 3 0.0019 T C 164 0.0756 VSR hCV31227848 rs11809423 T T 20.0015 1 0.0018 1 0.0012 T C 116 0.085 UCSFCCF hCV31573621 rs11079818 CC 164 0.0755 36 0.0633 128 0.0799 C T 895 0.4123 VSR hCV31573621rs11079818 C C 100 0.0745 30 0.056 70 0.0867 C T 539 0.4013 UCSFCCFhCV31705214 rs12804599 T T 116 0.0534 41 0.0721 75 0.0468 T A 752 0.3464VSR hCV31705214 rs12804599 T T 71 0.052 31 0.0564 40 0.0491 T A 4540.3326 UCSFCCF hCV32160712 rs11079160 T T 57 0.0263 17 0.0299 40 0.025 TA 629 0.29 VSR hCV32160712 rs11079160 T T 37 0.0273 20 0.0367 17 0.021 TA 358 0.2644 UCSFCCF hCV435733  rs10276935 G G 226 0.1042 65 0.1142 1610.1006 G C 894 0.4122 VSR hCV435733  rs10276935 G G 132 0.0968 46 0.083886 0.1057 G C 555 0.4072 UCSFCCF hCV454333  rs10916581 T T 42 0.0194 60.0106 36 0.0225 T C 506 0.2333 VSR hCV454333  rs10916581 T T 25 0.01845 0.0091 20 0.0248 T C 274 0.2019 UCSFCCF hCV540056  rs346802  T T 20.0009 1 0.0018 1 0.0006 T C 159 0.0733 VSR hCV540056  rs346802  T T 0 00 0 0 0 T C 90 0.0661 UCSFCCF hCV7917138  rs9822460  G G 94 0.0434 290.051 65 0.0407 G A 672 0.3101 VSR hCV7917138  rs9822460  G G 53 0.03929 0.0531 24 0.0296 G A 432 0.3181 UCSFCCF hCV8147903  rs680014  A A 1180.0544 25 0.0439 93 0.0581 A G 735 0.3387 VSR hCV8147903  rs680014  A A66 0.0486 21 0.0385 45 0.0554 A G 445 0.3277 UCSFCCF hCV8754449 rs781226  T T 137 0.0632 37 0.065 100 0.0625 T C 852 0.3928 VSRhCV8754449  rs781226  T T 73 0.0536 15 0.0274 58 0.0713 T C 460 0.338UCSFCCF hCV8820007  rs938390  A A 143 0.0659 29 0.0511 114 0.0712 A T769 0.3545 VSR hCV8820007  rs938390  A A 94 0.0693 28 0.0511 66 0.0816 AT 463 0.3412 UCSFCCF hCV8942032  rs1264352  C C 46 0.0212 14 0.0246 320.02 C G 518 0.2388 VSR hCV8942032  rs1264352  C C 34 0.0249 16 0.029218 0.0221 C G 298 0.2186 Case Case Control Control ALL ALL Case CaseControl Control Study Marker cnt frq cnt frq Genot cnt frq cnt frq cntfrq UCSFCCF hCV1053082  182 0.3199 506 0.3164 C C 1382 0.6375 370 0.65031012 0.6329 VSR hCV1053082  145 0.2646 251 0.3084 C C  914 0.6711 3870.7062 527 0.6474 UCSFCCF hCV1116757  158 0.2777 516 0.3225 T T 14100.6501 387 0.6801 1023 0.6394 VSR hCV1116757  138 0.2546 234 0.2936 T T 926 0.6916 391 0.7214 535 0.6713 UCSFCCF hCV11425801 284 0.4991 7860.4906 T T  602 0.2773 142 0.2496 460 0.2871 VSR hCV11425801 274 0.5009408 0.5025 T T  358 0.2634 133 0.2431 225 0.2771 UCSFCCF hCV11425842 2910.5123 785 0.4906 C C  606 0.2795 166 0.2923 440 0.275 VSR hCV11425842277 0.5055 415 0.5098 C C  387 0.2841 167 0.3047 220 0.2703 UCSFCCFhCV11548152 180 0.3163 423 0.2647 G G 1512 0.6977 374 0.6573 1138 0.7121VSR hCV11548152 150 0.2727 195 0.2393 G G  986 0.7223 383 0.6964 6030.7399 UCSFCCF hCV11738775 280 0.4921 778 0.4862 T T  832 0.3836 2320.4077 600 0.375 VSR hCV11738775 257 0.469  366 0.4502 T T  537 0.3946226 0.4124 311 0.3825 UCSFCCF hCV11758801 40 0.0704 83 0.0518 C C 20420.9414 526 0.9261 1516 0.9469 VSR hCV11758801 40 0.0727 43 0.0528 C C1280 0.9377 508 0.9236 772 0.9472 UCSFCCF hCV11861255 206 0.362  5440.3398 A A 1276 0.588  336 0.5905 940 0.5871 VSR hCV11861255 185 0.3413299 0.3724 A A  766 0.5695 327 0.6033 439 0.5467 UCSFCCF hCV12071939 1910.3357 550 0.3438 G G 1334 0.615  363 0.638 971 0.6069 VSR hCV12071939143 0.26  267 0.3284 G G  892 0.6544 382 0.6945 510 0.6273 UCSFCCFhCV1209800  38 0.0669 161 0.1005 G G 1967 0.9065 530 0.9331 1437 0.897VSR hCV1209800  34 0.0617 69 0.0847 G G 1259 0.9217 517 0.9383 7420.9104 UCSFCCF hCV1262973  92 0.1617 232 0.1449 G G 1817 0.8373 4660.819 1351 0.8438 VSR hCV1262973  117 0.2175 128 0.1572 G G 1091 0.807 416 0.7732 675 0.8292 UCSFCCF hCV1348610  289 0.5088 776 0.4853 G G  6280.2898 144 0.2535 484 0.3027 VSR hCV1348610  238 0.4457 383 0.4758 G G 417 0.3114 159 0.2978 258 0.3205 UCSFCCF hCV1408483  181 0.3181 4260.2662 C C 1506 0.6943 374 0.6573 1132 0.7075 VSR hCV1408483  188 0.3431238 0.2924 C C  886 0.6505 338 0.6168 548 0.6732 UCSFCCF hCV1452085  1050.1845 307 0.1918 C C 1730 0.7972 461 0.8102 1269 0.7926 VSR hCV1452085 84 0.1525 161 0.1975 C C 1104 0.8082 460 0.8348 644 0.7902 UCSFCCFhCV15851766 14 0.0246 73 0.0457 G G 2079 0.9597 554 0.9754 1525 0.9543VSR hCV15851766 15 0.0279 44 0.0549 G G 1281 0.956  523 0.9721 7580.9451 UCSFCCF hCV15857769 238 0.4183 652 0.4075 C C 1067 0.4919 2660.4675 801 0.5006 VSR hCV15857769 225 0.4098 349 0.4287 C C  683 0.5011271 0.4936 412 0.5061 UCSFCCF hCV15879601 66 0.116  241 0.1504 C C 18510.8526 501 0.8805 1350 0.8427 VSR hCV15879601 59 0.1075 96 0.1181 C C1199 0.8803 490 0.8925 709 0.8721 UCSFCCF hCV16134786 182 0.3204 4480.28 G G 1466 0.6762 364 0.6408 1102 0.6888 VSR hCV16134786 183 0.3327221 0.2712 G G  908 0.6652 345 0.6273 563 0.6908 UCSFCCF hCV1619596  2290.4025 597 0.3736 G G 1155 0.533  286 0.5026 869 0.5438 VSR hCV1619596 223 0.4055 286 0.3514 G G  772 0.566  290 0.5273 482 0.5921 UCSFCCFhCV16336   93 0.1634 314 0.196 C C 1733 0.7982 469 0.8243 1264 0.789 VSRhCV16336   93 0.1697 171 0.2101 C C 1083 0.7952 453 0.8266 630 0.774UCSFCCF hCV1723718  255 0.4482 683 0.4271 G G 1031 0.4756 253 0.4446 7780.4866 VSR hCV1723718  230 0.4189 303 0.3722 G G  707 0.5187 266 0.4845441 0.5418 UCSFCCF hCV1958451  196 0.3445 607 0.3796 G G 1230 0.5673 3430.6028 887 0.5547 VSR hCV1958451  194 0.3553 302 0.3715 G G  773 0.5688325 0.5952 448 0.551 UCSFCCF hCV2121658  108 0.1905 380 0.2375 G G 16560.7642 453 0.7989 1203 0.7519 VSR hCV2121658  113 0.2096 182 0.2244 G G1037 0.7681 423 0.7848 614 0.7571 UCSFCCF hCV2358247  84 0.1479 1780.1112 A A 1892 0.8727 482 0.8486 1410 0.8812 VSR hCV2358247  67 0.121673 0.0896 A A 1221 0.8939 479 0.8693 742 0.9104 UCSFCCF hCV2390937  660.116  228 0.1424 C C 1864 0.859  501 0.8805 1363 0.8513 VSR hCV2390937 58 0.1055 121 0.1485 C C 1183 0.8667 491 0.8927 692 0.8491 UCSFCCFhCV25473186 296 0.5202 772 0.4819 T T  615 0.2833 138 0.2425 477 0.2978VSR hCV25473186 291 0.532  398 0.4883 T T  427 0.3135 147 0.2687 2800.3436 UCSFCCF hCV25596936 88 0.1547 194 0.1211 C C 1876 0.8641 4790.8418 1397 0.872 VSR hCV25596936 104 0.1891 107 0.1316 C C 1137 0.8342439 0.7982 698 0.8585 UCSFCCF hCV25615822 33 0.0581 79 0.0493 C C 20560.9479 534 0.9401 1522 0.9507 VSR hCV25615822 54 0.098  55 0.0676 C C1254 0.9187 496 0.9002 758 0.9312 UCSFCCF hCV25983294 152 0.2676 5190.324 G G 1424 0.6562 397 0.6989 1027 0.6411 VSR hCV25983294 151 0.275 262 0.3227 G G  884 0.6495 375 0.6831 509 0.6268 UCSFCCF hCV2637554  2400.4233 673 0.4209 T T 1063 0.4908 263 0.4638 800 0.5003 VSR hCV2637554 237 0.4357 327 0.4037 T T  651 0.4808 244 0.4485 407 0.5025 UCSFCCFhCV26478797 204 0.3585 652 0.4078 G G 1190 0.5489 334 0.587 856 0.5353VSR hCV26478797 214 0.3919 317 0.3899 G G  733 0.5394 304 0.5568 4290.5277 UCSFCCF hCV26881276 260 0.4577 669 0.4184 A A  988 0.4559 2420.4261 746 0.4665 VSR hCV26881276 246 0.4473 351 0.4307 A A  585 0.4286218 0.3964 367 0.4503 UCSFCCF hCV27077072 233 0.4095 722 0.451 C C  9780.4507 276 0.4851 702 0.4385 VSR hCV27077072 238 0.4327 369 0.4533 C C 605 0.4435 258 0.4691 347 0.4263 UCSFCCF hCV27473671 249 0.4376 6550.4089 T T 1084 0.4993 266 0.4675 818 0.5106 VSR hCV27473671 222 0.4036310 0.3818 T T  727 0.5338 277 0.5036 450 0.5542 UCSFCCF hCV27494483 640.1125 138 0.0862 C C 1956 0.9014 501 0.8805 1455 0.9088 VSR hCV2749448359 0.1073 62 0.0763 C C 1239 0.909  489 0.8891 750 0.9225 UCSFCCFhCV27504565 199 0.3497 660 0.4128 C C 1171 0.5401 331 0.5817 840 0.5253VSR hCV27504565 187 0.3394 273 0.335 C C  839 0.6142 351 0.637 48880.5988 UCSFCCF hCV27511436 147 0.2602 430 0.2701 T T 1525 0.707  4130.731 1112 0.6985 VSR hCV27511436 141 0.2564 239 0.2933 T T  938 0.6872393 0.7145 545 0.6687 UCSFCCF hCV2769503  278 0.4886 711 0.4441 A A  9280.4276 217 0.3814 711 0.4441 VSR hCV2769503  263 0.4907 336 0.4164 A A 598 0.4453 208 0.3881 390 0.4833 UCSFCCF hCV27892569 219 0.3856 5770.362 T T 1253 0.5796 314 0.5528 939 0.5891 VSR hCV27892569 200 0.363 250 0.3086 T T  823 0.6047 317 0.5753 506 0.6247 UCSFCCF hCV28036404 1820.321  495 0.309 T T 1393 0.6422 368 0.649 1025 0.6398 VSR hCV28036404156 0.2857 277 0.3403 T T  888 0.6529 377 0.6905 511 0.6278 UCSFCCFhCV2851380  91 0.1602 295 0.1841 G G 1752 0.8074 473 0.8327 1279 0.7984VSR hCV2851380  99 0.18  179 0.2199 G G 1065 0.7808 444 0.8073 6210.7629 UCSFCCF hCV29401764 223 0.3919 733 0.4584 C C  989 0.4562 2840.4991 705 0.4406 VSR hCV29401764 221 0.4048 374 0.4595 C C  606 0.4456267 0.489 339 0.4165 UCSFCCF hCV29537898 100 0.1761 247 0.1545 C C 17970.8293 458 0.8063 1339 0.8374 VSR hCV29537898 90 0.1657 114 0.1402 C C1146 0.8451 448 0.825 698 0.8585 UCSFCCF hCV29538757 214 0.3768 7130.4453 C C 1050 0.4841 305 0.537 745 0.4653 VSR hCV29538757 226 0.4117372 0.457 C C  629 0.4615 277 0.5046 352 0.5324 UCSFCCF hCV302629  2230.3926 654 0.4088 A A 1106 0.5101 277 0.4877 829 0.5181 VSR hCV302629 209 0.3842 332 0.4094 A A  703 0.5188 280 0.5147 423 0.5216 UCSFCCFhCV30308202 185 0.3251 530 0.3315 G G 1352 0.6236 367 0.645 985 0.616VSR hCV30308202 150 0.2742 267 0.328 G G  878 0.6451 372 0.6801 5060.6216 UCSFCCF hCV3054550  155 0.2724 386 0.2409 C C 1580 0.7278 3970.6977 1183 0.7385 VSR hCV3054550  161 0.2922 201 0.2466 C C  968 0.7086376 0.6824 592 0.7264 UCSFCCF hCV3082219  134 0.2355 317 0.198 G G 16920.7797 428 0.7522 1264 0.7895 VSR hCV3082219  137 0.2532 165 0.203 G G1031 0.7614 393 0.7264 638 0.7847 UCSFCCF hCV31137507 234 0.4112 6070.3789 G G 1168 0.538  288 0.5062 880 0.5493 VSR hCV31137507 225 0.4106314 0.3857 G G  722 0.5301 277 0.5055 445 0.5467 UCSFCCF hCV31227848 590.1037 105 0.0656 C C 2002 0.9226 509 0.8946 1493 0.9325 VSR hCV3122784862 0.1129 54 0.0663 C C 1246 0.9135 486 0.8852 760 0.9325 UCSFCCFhCV31573621 223 0.3919 672 0.4195 T T 1112 0.5122 310 0.5448 802 0.5006VSR hCV31573621 216 0.403  323 0.4002 T T  704 0.5242 290 0.541 4140.513 UCSFCCF hCV31705214 201 0.3533 551 0.3439 A A 1303 0.6002 3270.5747 976 0.6092 VSR hCV31705214 204 0.3709 250 0.3067 A A  840 0.6154315 0.5727 525 0.6442 UCSFCCF hCV32160712 187 0.3286 442 0.2762 A A 14830.6837 365 0.6415 1118 0.6988 VSR hCV32160712 151 0.2771 207 0.2559 A A 959 0.7083 374 0.6862 585 0.7231 UCSFCCF hCV435733  253 0.4446 6410.4006 C C 1049 0.4836 251 0.4411 798 0.4988 VSR hCV435733  253 0.4608302 0.371 C C  676 0.496  250 0.4554 426 0.5233 UCSFCCF hCV454333  1270.2236 379 0.2367 C C 1621 0.7473 435 0.7658 1186 0.7408 VSR hCV454333 100 0.1815 174 0.2159 C C 1058 0.7797 446 0.8094 612 0.7593 UCSFCCFhCV540056  30 0.0527 129 0.0806 C C 2009 0.9258 538 0.9455 1471 0.9188VSR hCV540056  26 0.0474 64 0.0787 C C 1272 0.9339 523 0.9526 749 0.9213UCSFCCF hCV7917138  197 0.3462 475 0.2972 A A 1401 0.6465 343 0.60281058 0.6621 VSR hCV7917138  173 0.3168 259 0.319 A A  873 0.6429 3440.63 529 0.6515 UCSFCCF hCV8147903  175 0.3076 560 0.3498 G G 13170.6069 369 0.6485 948 0.5921 VSR hCV8147903  172 0.3156 273 0.3358 G G 847 0.6237 352 0.6459 495 0.6089 UCSFCCF hCV8754449  203 0.3568 6490.4056 C C 1180 0.544  329 0.5782 851 0.5319 VSR hCV8754449  188 0.3431272 0.3346 C C  828 0.6084 345 0.6296 483 0.5941 UCSFCCF hCV8820007  2070.3644 562 0.351 T T 1257 0.5795 332 0.5845 925 0.5778 VSR hCV8820007 178 0.3248 285 0.3523 T T  800 0.5895 342 0.6241 458 0.5661 UCSFCCFhCV8942032  151 0.2654 367 0.2294 G G 1605 0.74  404 0.71 1201 0.7506VSR hCV8942032  133 0.2427 165 0.2025 G G 1031 0.7564 399 0.7281 6320.7755

TABLE 19C HW (Control) allelicAsc allelicAsc allelicAsc DomGenotAscDomGenotAsc RecGenotAsc RecGenotAsc AddGenotAsc AddGenotAsc OR.Hom.Study Marker rs pExact chi2 pAsym pExact chi2 pAsym chi2 pAsym chi2pAsym OR.Hom 95CI.L UCSF hCV1053082  rs544115  9.57E−02 1.8813 1.70E−011.84E−01 0.5478 4.59E−01 4.1986 4.05E−02 1.8401 1.75E−01 0.574 0.3358CCF VSR hCV1053082  rs544115  3.79E−01 5.9535 1.47E−02 1.54E−02 5.12722.36E−02 2.0145 1.56E−01 5.7805 1.62E−02 0.6052 0.331 UCSF hCV1116757 rs3794971  7.54E−01 1.8049 1.79E−01 1.91E−01 3.0663 7.99E−02 0.18326.69E−01 1.7897 1.81E−01 1.04 0.6394 CCF VSR hCV1116757  rs3794971 7.21E−01 4.3026 0.0381 0.0407 3.8015 0.0512 1.3504 0.2450 4.246 0.03930.6353 0.3249 UCSF hCV11425801 rs3805953  5.81E−01 3.7417 5.31E−025.74E−02 2.959 8.54E−02 2.008 1.56E−01 3.6971 5.45E−02 1.3012 0.993 CCFVSR hCV11425801 rs3805953  8.33E−01 3.1552 7.57E−02 7.83E−02 1.94141.64E−01 2.2927 1.30E−01 3.1695 7.50E−02 1.3231 0.9724 UCSF hCV11425842rs10948059 5.15E−01 2.6567 1.03E−01 1.04E−01 0.6196 4.31E−01 3.65715.58E−02 2.6452 1.04E−01 0.7846 0.5948 CCF VSR hCV11425842 rs109480595.74E−01 2.7491 9.73E−02 9.99E−02 1.9136 1.67E−01 1.8051 1.79E−01 2.81139.36E−02 0.7654 0.5589 UCSF hCV11548152 rs11580249 8.49E−01 5.17952.29E−02 2.49E−02 5.9849 1.44E−02 0.1844 6.68E−01 5.2806 2.16E−02 1.23360.6694 CCF VSR hCV11548152 rs11580249 7.72E−01 3.669 5.54E−02 5.68E−023.1002 7.83E−02 1.3657 2.43E−01 3.6121 5.74E−02 1.5744 0.7942 UCSFhCV11738775 rs6754561  2.44E−01 4.5652 3.26E−02 3.52E−02 1.902 1.68E−015.5721 1.82E−02 4.7722 2.89E−02 0.664 0.4783 CCF VSR hCV11738775rs6754561  1.22E−01 4.301 3.81E−02 3.97E−02 1.223 2.69E−01 6.15991.31E−02 4.1958 4.05E−02 0.6577 0.4674 UCSF hCV11758801 rs118419973.28E−01 3.8274 5.04E−02 5.52E−02 3.307 6.90E−02 1.1756 2.78E−01 3.70935.41E−02 2.8821 0.405 CCF VSR hCV11758801 rs11841997 1.00E+00 3.94874.69E−02 5.84E−02 3.133 7.67E−02 2.968 8.49E−02 3.892 4.85E−02 UCSFhCV11861255 rs529407  2.74E−03 0.9704 3.25E−01 3.32E−01 0.0198 8.87E−014.4502 3.49E−02 0.9239 3.36E−01 0.6456 0.4172 CCF VSR hCV11861255rs529407  1.76E−01 5.8243 1.58E−02 1.62E−02 4.2314 3.97E−02 3.22967.23E−02 5.5905 1.81E−02 0.6196 0.3928 UCSF hCV12071939 rs1950943 9.42E−01 3.6497 5.61E−02 5.84E−02 1.7131 1.91E−01 5.3616 2.06E−02 3.70535.42E−02 0.5079 0.2887 CCF VSR hCV12071939 rs1950943  9.15E−01 4.5583.28E−02 3.42E−02 6.5586 1.04E−02 0.0106 9.15E−01 4.3724 3.65E−02 0.92710.5472 UCSF hCV1209800  rs35067690 1.00E+00 6.8747 8.74E−03 9.31E−036.4426 1.11E−02 1.4208 2.33E−01 6.9406 8.43E−03 0 CCF VSR hCV1209800 rs35067690 9.86E−02 4.5292 3.33E−02 3.77E−02 3.5355 6.01E−02 2.71229.96E−02 4.3855 3.62E−02 0 UCSF hCV1262973  rs229653  3.31E−02 2.84019.19E−02 9.99E−02 1.9058 1.67E−01 2.0833 1.49E−01 2.6543 1.03E−01 1.77170.8307 CCF VSR hCV1262973  rs229653  9.20E−02 4.7235 2.98E−02 3.25E−026.5217 1.07E−02 0.4932 4.82E−01 4.6556 3.10E−02 0.7375 0.2545 UCSFhCV1348610  rs3739636  3.92E−01 4.7184 2.98E−02 3.18E−02 4.9229 2.65E−021.6159 2.04E−01 4.6621 3.08E−02 1.3385 1.019 CCF VSR hCV1348610 rs3739636  3.18E−01 3.6947 5.46E−02 5.73E−02 0.7744 3.79E−01 5.14132.34E−02 3.4678 6.26E−02 1.3555 1.0033 UCSF hCV1408483  rs170708487.80E−01 3.5792 5.85E−02 6.33E−02 4.9851 2.56E−02 0.0452 8.31E−01 3.62255.70E−02 1.0089 0.5449 CCF VSR hCV1408483  rs17070848 7.23E−01 4.06334.38E−02 4.77E−02 4.5874 3.22E−02 0.306 5.80E−01 4.0784 4.34E−02 1.27390.7171 UCSF hCV1452085  rs12223005 2.06E−01 1.6991 1.92E−01 2.01E−010.8011 3.71E−01 3.5259 6.04E−02 1.6769 1.95E−01 0.3303 0.0993 CCF VSRhCV1452085  rs12223005 1.00E+00 3.5065 6.11E−02 6.21E−02 4.2302 3.97E−020.005 9.36E−01 3.431 6.40E−02 0.98 0.3703 UCSF hCV15851766 rs2229995 1.00E+00 4.7105 3.00E−02 3.54E−02 4.8091 2.83E−02 4.8091 2.83E−02 CCFVSR hCV15851766 rs2229995  1.00E+00 5.444 1.96E−02 2.19E−02 5.56931.83E−02 5.5693 1.83E−02 UCSF hCV15857769 rs2924914  4.01E−01 3.06138.02E−02 8.41E−02 1.8442 1.74E−01 2.3797 1.23E−01 2.9769 8.45E−02 1.33150.9638 CCF VSR hCV15857769 rs2924914  8.13E−02 1.5429 2.14E−01 2.27E−010.2055 6.50E−01 4.5155 3.36E−02 1.5844 2.08E−01 1.5203 1.0085 UCSFhCV15879601 rs2275769  8.69E−01 5.0195 2.51E−02 2.73E−02 4.7726 2.89E−020.7923 3.73E−01 5.012 2.52E−02 0.4899 0.1082 CCF VSR hCV15879601rs2275769  4.68E−02 2.5557 1.10E−01 1.26E−01 1.3012 2.54E−01 5.43411.97E−02 2.4744 1.16E−01 0 UCSF hCV16134786 rs2857595  5.97E−01 4.38473.63E−02 3.81E−02 4.3936 3.61E−02 0.7309 3.93E−01 4.3449 3.71E−02 1.33210.7957 CCF VSR hCV16134786 rs2857595  1.14E−01 4.6354 3.13E−02 3.54E−025.9503 1.47E−02 0.0339 8.53E−01 4.5185 3.35E−02 1.1581 0.6598 UCSFhCV1619596  rs1048621  4.21E−02 2.9988 8.33E−02 8.94E−02 2.857 9.10E−020.809 3.68E−01 2.8638 9.06E−02 1.243 0.8815 CCF VSR hCV1619596 rs1048621  6.94E−01 5.0407 2.48E−02 2.67E−02 5.6219 1.77E−02 0.66524.15E−01 5.0508 2.46E−02 1.3369 0.8468 UCSF hCV16336   rs362277 3.82E−01 3.1329 7.67E−02 8.47E−02 3.2376 7.20E−02 0.2141 6.44E−01 3.05028.07E−02 0.7861 0.3365 CCF VSR hCV16336   rs362277  7.41E−01 7.18767.34E−03 8.10E−03 5.5815 1.82E−02 4.5646 3.26E−02 7.2354 7.15E−03 0.2140.048 UCSF hCV1723718  rs12481805 5.13E−01 3.8839 4.88E−02 5.19E−022.9562 8.56E−02 2.1993 1.38E−01 3.9421 4.71E−02 1.3593 0.9742 CCF VSRhCV1723718  rs12481805 9.24E−02 3.6917 5.47E−02 5.72E−02 4.3047 3.80E−020.444 5.05E−01 3.5428 5.98E−02 1.2553 0.8516 UCSF hCV1958451  rs2985822 9.48E−01 4.1971 4.05E−02 4.14E−02 3.9539 4.68E−02 1.2038 2.73E−01 4.1744.10E−02 0.7389 0.4833 CCF VSR hCV1958451  rs2985822  2.40E−01 4.56043.27E−02 3.35E−02 2.6009 1.07E−01 4.153 4.16E−02 4.4562 3.48E−02 0.59080.3682 UCSF hCV2121658  rs1187332  3.41E−02 4.3002 3.81E−02 4.02E−025.1465 2.33E−02 0.0001 9.61E−01 4.49 3.41E−02 0.9373 0.3672 CCF VSRhCV2121658  rs1187332  7.57E−01 2.4843 1.15E−01 1.20E−01 1.3947 2.38E−014.1148 4.25E−02 2.5241 1.12E−01 0.2903 0.0835 UCSF hCV2358247  rs415989 3.03E−02 2.7624 9.65E−02 9.75E−02 4.0243 4.48E−02 1.0344 3.09E−01 2.67721.02E−01 0.4876 0.1087 CCF VSR hCV2358247  rs415989  4.00E−01 7.97494.74E−03 6.00E−03 5.853 1.56E−02 7.4228 6.44E−03 7.8768 5.01E−03 UCSFhCV2390937  rs739719  8.61E−01 3.1417 7.63E−02 8.49E−02 2.9448 8.62E−020.5694 4.50E−01 3.1343 7.67E−02 0.5441 0.1188 CCF VSR hCV2390937 rs739719  2.18E−01 5.0969 2.40E−02 2.44E−02 5.414 2.00E−02 0.06058.05E−01 5.2977 2.14E−02 0.7047 0.0637 UCSF hCV25473186 rs2880415 2.28E−01 4.3841 3.63E−02 3.81E−02 6.3063 1.20E−02 0.6889 4.07E−01 4.32893.75E−02 1.3219 1.0048 CCF VSR hCV25473186 rs2880415  8.85E−01 7.48636.22E−03 6.51E−03 8.5136 3.52E−03 2.1489 1.43E−01 7.7174 5.47E−03 1.51551.0992 UCSF hCV25596936 rs6967117  1.59E−01 2.2975 1.30E−01 1.39E−013.2629 7.09E−02 0.7923 3.73E−01 2.2646 1.32E−01 0.5303 0.1171 CCF VSRhCV25596936 rs6967117  1.24E−01 8.1435 4.32E−03 4.78E−03 8.6432 3.28E−030.2513 6.16E−01 7.8335 5.13E−03 1.3912 0.501 UCSF hCV25615822 NONE6.23E−01 1.2345 2.67E−01 2.80E−01 0.9387 3.33E−01 2.82 9.31E−02 1.24572.64E−01 CCF VSR hCV25615822 NONE 1.00E+00 4.1369 4.20E−02 4.98E−024.2329 3.96E−02 0.0772 7.81E−01 4.1629 4.13E−02 1.5282 0.0954 UCSFhCV25983294 rs3739709  3.85E−01 4.819 2.81E−02 3.07E−02 6.2248 1.26E−020.0285 8.65E−01 4.8577 2.75E−02 0.8777 0.515 CCF VSR hCV25983294rs3739709  3.44E−01 4.3198 3.77E−02 3.98E−02 4.5466 3.30E−02 0.54044.62E−01 4.1249 4.23E−02 0.7614 0.4492 UCSF hCV2637554  rs3205421 3.62E−01 4.974 2.57E−02 2.85E−02 2.2274 1.36E−01 6.0734 1.37E−02 5.00672.52E−02 1.5451 1.1091 CCF VSR hCV2637554 rs3205421  3.99E−01 4.37763.64E−02 3.80E−02 3.793 5.15E−02 1.707 1.91E−01 4.2587 3.90E−02 1.38270.9553 UCSF hCV26478797 rs2015018  2.31E−02 3.2424 7.18E−02 7.43E−024.5232 3.34E−02 0.0466 8.29E−01 3.3871 6.57E−02 0.8731 0.5698 CCF VSRhCV26478797 rs2015018  4.32E−01 3.0398 8.12E−02 8.40E−02 1.1134 2.91E−014.8681 2.74E−02 3.047 8.09E−02 0.5897 0.3705 UCSF hCV26881276 rs2344829 7.67E−02 1.6418 2.00E−01 2.12E−01 2.7694 9.61E−02 0.0052 9.35E−01 1.59382.07E−01 1.1057 0.8058 CCF VSR hCV26881276 rs2344829  3.46E−01 5.99311.44E−02 1.60E−02 3.9019 4.82E−02 3.9451 4.70E−02 5.7504 1.65E−02 1.49261.0675 UCSF hCV27077072 rs8060368  6.95E−01 2.5397 1.11E−01 1.14E−013.68 5.51E−02 0.1126 7.37E−01 2.5305 1.12E−01 0.8622 0.6234 CCF VSRhCV27077072 rs8060368  1.00E+00 3.1185 7.74E−02 8.22E−02 2.4362 1.19E−011.6353 2.01E−01 3.0097 7.74E−02 0.7411 0.5123 UCSF hCV27473671rs3750465  9.51E−01 3.3546 6.70E−02 6.87E−02 3.1234 7.72E−02 1.12472.89E−01 3.3751 6.62E−02 1.2873 0.9103 CCF VSR hCV27473671 rs3750465 9.27E−01 5.2115 2.24E−02 2.50E−02 3.367 6.65E−02 3.8604 4.94E−02 5.15352.32E−02 1.5933 1.0529 UCSF hCV27494483 rs3748743  2.72E−02 3.91634.78E−02 5.21E−02 3.7863 5.17E−02 0.3155 5.74E−01 3.7048 5.43E−02 1.45210.4354 CCF VSR hCV27494483 rs3748743  1.00E+00 4.7395 2.95E−02 3.30E−024.4302 3.53E−02 0.865 3.52E−01 4.7363 2.95E−02 3.0675 0.2774 UCSFhCV27504565 rs3219489  4.17E−02 2.6893 1.01E−01 1.07E−01 5.3732 2.04E−020.3093 5.78E−01 2.7588 9.67E−02 0.9997 0.6757 CCF VSR hCV27504565rs3219489  6.37E−02 6.3249 1.19E−02 1.22E−02 2.0298 1.54E−01 12.8293.41E−04 6.2596 1.24E−02 0.3347 0.1799 UCSF hCV27511436 rs3750145 2.79E−01 4.7174 2.99E−02 2.96E−02 2.1238 1.45E−01 8.5394 3.48E−03 4.71252.99E−02 0.2692 0.1066 CCF VSR hCV27511436 rs3750145  4.85E−01 3.4346.39E−02 7.13E−02 3.2092 7.32E−02 0.7905 3.74E−01 3.3344 6.78E−02 0.71580.3861 UCSF hCV2769503  rs4787956  9.55E−01 6.0949 1.36E−02 1.50E−026.7483 9.38E−03 1.3572 2.44E−01 6.1512 1.31E−02 1.3545 0.9929 CCF VSRhCV2769503  rs4787956  5.09E−01 9.7933 1.75E−03 1.95E−03 11.821 5.86E−041.4515 2.28E−01 9.8523 1.70E−03 1.5046 1.0422 UCSF hCV27892569rs4903741  3.97E−01 2.7801 9.54E−02 9.57E−02 2.2605 1.33E−01 1.36062.43E−01 2.8366 9.21E−02 1.3419 0.8828 CCF VSR hCV27892569 rs4903741 4.12E−03 1.8263 1.77E−01 1.79E−01 3.3443 6.74E−02 0.1334 7.15E−01 1.71251.91E−01 1.005 0.6399 UCSF hCV28036404 rs4812768  3.21E−02 1.20242.73E−01 2.82E−01 0.1544 6.94E−01 4.3224 3.76E−02 1.1665 2.80E−01 0.57740.3379 CCF VSR hCV28036404 rs4812768  1.28E−01 5.3749 2.04E−02 2.13E−025.6716 1.72E−02 0.7758 3.78E−01 5.6186 1.78E−02 0.6777 0.3437 UCSFhCV2851380  rs12445805 2.89E−02 4.529 3.33E−02 3.60E−02 3.185 7.43E−023.1432 7.62E−02 4.3423 3.72E−02 0.3863 0.1348 CCF VSR hCV2851380 rs12445805 7.53E−01 3.7815 5.18E−02 5.25E−02 3.776 5.20E−02 0.4335.11E−01 3.7227 5.37E−02 0.6993 0.28 UCSF hCV29401764 rs7793552 1.57E−01 2.3924 1.22E−01 1.30E−01 5.7341 1.66E−02 0.3114 5.77E−01 2.4111.20E−01 0.956 0.6916 CCF VSR hCV29401764 rs7793552  9.39E−01 5.98821.44E−02 1.46E−02 6.9627 8.32E−03 1.0087 3.15E−01 5.8764 1.53E−02 0.72910.5084 UCSF CCF hCV29537898 rs6073804  6.31E−01 4.1761 4.10E−02 4.70E−022.8557 9.10E−02 3.5835 5.84E−02 4.0584 4.40E−02 2.2489 0.9794 VSRhCV29537898 rs6073804  1.14E−01 3.821 5.06E−02 5.96E−02 2.7919 9.47E−024.704 3.01E−02 3.9237 4.76E−02 7.7902 0.9071 UCSF hCV29539757 rs101106591.46E−01 5.5454 1.85E−02 1.97E−02 8.6151 3.33E−03 0.0484 8.25E−01 5.62031.78E−02 0.837 0.5894 CCF VSR hCV29539757 rs10110659 6.39E−01 7.3796.60E−03 7.33E−03 6.8624 8.80E−03 2.6171 1.06E−01 7.4502 6.34E−03 0.64950.4404 UCSF hCV302629  rs9284183  4.55E−01 6.072 1.37E−02 1.46E−021.5552 2.12E−01 11.66 6.39E−04 5.9952 1.43E−02 1.7394 1.2525 CCF VSRhCV302629  rs9284183  4.28E−01 1.2194 2.69E−01 2.76E−01 0.0616 8.04E−014.4477 3.49E−02 1.2037 2.73E−01 1.4837 0.993 UCSF hCV30308202 rs9482985 2.71E−01 3.3551 6.70E−02 6.92E−02 1.5017 2.20E−01 4.8497 2.76E−02 3.31816.85E−02 0.5432 0.3182 CCF VSR hCV30308202 rs9482985  4.66E−01 4.04724.42E−02 4.58E−02 4.8822 2.71E−02 0.1543 6.94E−01 3.8598 4.95E−02 0.82940.4955 UCSF hCV3054550  rs1559599  8.36E−01 4.1733 4.11E−02 4.60E−023.5169 6.07E−02 1.6062 2.05E−01 4.1327 4.21E−02 1.5351 0.8458 CCF VSRhCV3054550  rs1559599  3.36E−01 2.2114 1.37E−01 1.50E−01 3.0804 7.92E−020.0322 8.57E−01 2.193 1.39E−01 1.0019 0.5064 UCSF hCV3082219  rs1884833 1.00E+00 2.8129 9.35E−02 9.54E−02 3.4024 6.51E−02 0.0012 9.55E−01 2.84329.18E−02 1.0336 0.434 CCF VSR hCV3082219  rs1884833  1.00E+00 6.44741.11E−02 1.33E−02 6.0815 1.37E−02 1.3727 2.41E−01 6.4841 1.09E−02 1.78580.7515 UCSF hCV31137507 rs7660668  4.76E−01 3.1157 7.75E−02 7.98E−023.147 7.61E−02 0.7113 3.99E−01 3.0745 7.95E−02 1.2488 0.8674 CCF VSRhCV31137507 rs7660668  1.00E+00 2.7419 9.77E−02 1.04E−01 2.2328 1.35E−011.279 2.58E−01 2.7397 9.79E−02 1.3436 0.8834 UCSF hCV31227848 rs118094234.36E−01 7.9108 4.91E−03 6.04E−03 8.4827 3.59E−03 0.0031 9.45E−01 7.85455.07E−03 0.9777 0.1015 CCF VSR hCV31227848 rs11809423 1.00E+00 8.93522.80E−03 3.13E−03 9.2748 2.32E−03 0.0792 7.78E−01 9.0359 2.65E−03 1.56380.0976 UCSF hCV31573621 rs11079818 4.66E−01 3.8384 5.01E−02 5.05E−023.2818 7.01E−02 1.663 1.97E−01 3.9118 4.79E−02 0.7276 0.4915 CCF VSRhCV31573621 rs11079818 5.47E−01 2.7923 9.47E−02 1.03E−01 1.0148 3.14E−014.4251 3.54E−02 2.8097 9.37E−02 0.6118 0.3888 UCSF hCV31705214rs12804599 8.84E−01 4.2814 3.85E−02 3.94E−02 2.0882 1.48E−01 5.28852.15E−02 4.2313 3.97E−02 1.6316 1.0929 CCF VSR hCV31705214 rs128045991.58E−01 5.9636 1.46E−02 1.60E−02 7.0819 7.79E−03 0.3533 5.52E−01 5.81521.59E−02 1.2917 0.7918 UCSF hCV32160712 rs11079160 7.14E−01 5.71121.69E−02 1.94E−02 6.367 1.16E−02 0.3901 5.32E−01 5.8369 1.57E−02 1.30180.7291 CCF VSR hCV32160712 rs11079160 8.90E−01 3.3547 6.70E−02 6.90E−022.1431 1.43E−01 3.0135 8.26E−02 3.3083 6.89E−02 1.8402 0.9516 UCSFhCV435733  rs10276935 5.73E−02 4.9763 2.57E−02 2.77E−02 5.5811 1.82E−020.833 3.61E−01 4.7987 2.85E−02 1.2836 0.9311 CCF VSR hCV435733 rs10276935 4.96E−03 1.658 1.98E−01 2.02E−01 6.059 1.38E−02 1.79171.81E−01 1.6077 2.05E−01 0.9114 0.6167 UCSF hCV454333  rs109165814.08E−01 2.4396 1.18E−01 1.31E−01 1.3942 2.38E−01 3.1385 7.65E−02 2.42181.20E−01 0.4544 0.1901 CCF VSR hCV454333  rs10916581 9.04E−02 6.75389.35E−03 9.52E−03 4.7879 2.87E−02 4.4834 3.42E−02 6.4961 1.08E−02 0.3430.1278 UCSF hCV540056  rs346802  5.17E−01 3.8011 5.12E−02 5.63E−024.3627 3.67E−02 0.5851 4.44E−01 3.8532 4.97E−02 2.7342 0.1707 CCF VSRhCV540056  rs346802  6.30E−01 5.0445 2.47E−02 2.84E−02 5.223 2.23E−025.223 2.23E−02 UCSF hCV7917138  rs9822460  2.21E−01 6.3815 1.15E−021.21E−02 6.4489 1.11E−02 1.0708 3.01E−01 6.2249 1.26E−02 1.3762 0.8737CCF VSR hCV7917138  rs9822460  3.02E−01 2.0808 1.49E−01 1.55E−01 0.65374.19E−01 4.8306 2.80E−02 2.0835 1.49E−01 1.8582 1.0639 UCSF hCV8147903 rs680014  4.01E−01 6.0117 1.42E−02 1.45E−02 5.5927 1.80E−02 1.63512.01E−01 5.8658 1.54E−02 0.6906 0.437 CCF VSR hCV8147903  rs680014 3.63E−01 2.8258 9.28E−02 9.42E−02 1.9048 1.68E−01 1.996 1.58E−01 2.76849.61E−02 0.6562 0.3841 UCSF hCV8754449  rs781226  1.09E−01 2.09541.48E−01 1.56E−01 3.6323 5.67E−02 0.0453 8.31E−01 2.1424 1.43E−01 0.95710.6428 CCF VSR hCV8754449  rs781226  2.62E−02 5.9675 1.46E−02 1.46E−021.7282 1.89E−01 12.467 4.14E−04 5.8303 1.58E−02 0.3621 0.2018 UCSFhCV8820007  rs938390  2.66E−02 0.8237 3.64E−01 3.76E−01 0.0782 7.79E−012.764 9.64E−02 0.7944 3.73E−01 0.7088 0.4627 CCF VSR hCV8820007 rs938390  2.72E−02 7.008 8.11E−03 8.99E−03 4.5349 3.32E−02 4.70993.00E−02 6.5843 1.03E−02 0.5681 0.3573 UCSF hCV8942032  rs1264352 5.20E−01 3.55 5.95E−02 6.61E−02 3.5971 5.79E−02 0.4287 5.13E−01 3.50836.11E−02 1.3006 0.6871 CCF VSR hCV8942032  rs1264352  7.41E−02 4.18194.09E−02 4.49E−02 3.9886 4.58E−02 0.6813 4.09E−01 3.947 4.70E−02 1.4080.7097 G OR.Hom. OR.Het. OR.Het. G Statistic std.ln OR99CI. OR99CI.OR95CI. OR95CI. Study Marker 95CI.U OR.Het 95CI.L 95CI.U Statistic pAsymOR (OR) L U L U UCSF hCV1053082  0.9814 0.9838 0.7998 1.2101 4.56881.02E−01 0.8873 0.0872 0.7088 1.1108 0.7479 1.0527 CCF VSR hCV1053082 1.1065 0.7867 0.617  1.003 5.8263 5.43E−02 0.7782 0.103 0.5969 1.01450.636 0.9521 UCSF hCV1116757  1.6918 0.8094 0.654  1.0017 3.99681.36E−01 0.8876 0.0888 0.7061 1.1157 0.7458 1.0563 CCF VSR hCV1116757 1.2422 0.8069 0.63  1.0336 4.2673 1.18E−01 0.8016 0.1068 0.6088 1.05530.6502 0.9881 UCSF hCV11425801 1.7051 1.1705 0.9281 1.4761 3.76021.53E−01 1.1429 0.0691 0.9566 1.3654 0.9982 1.3085 CCF VSR hCV114258011.8004 1.1361 0.873  1.4785 3.1782 2.04E−01 1.1491 0.0783 0.9393 1.40590.9857 1.3397 UCSF hCV11425842 1.035  0.9826 0.7858 1.2287 3.75371.53E−01 0.8932 0.0693 0.7471 1.0678 0.7797 1.0232 CCF VSR hCV114258421.0482 0.8793 0.6833 1.1315 2.8121 2.45E−01 0.878 0.0785 0.7173 1.07470.7528 1.024 UCSF hCV11548152 2.273  1.2948 1.0496 1.5973 5.87745.29E−02 1.2289 0.0907 0.9729 1.5522 1.0288 1.4679 CCF VSR hCV115481523.1213 1.2111 0.9447 1.5526 3.5834 1.67E−01 1.2289 0.1077 0.9311 1.6220.995 1.5179 UCSF hCV11738775 0.9219 0.9308 0.759  1.1414 6.296 4.29E−020.8572 0.0722 0.7118 1.0323 0.7442 0.9874 CCF VSR hCV11738775 0.92550.9663 0.7646 1.2211 6.3672 4.14E−02 0.8453 0.0811 0.686 1.0416 0.72110.9909 UCSF hCV11758801 20.513  1.389 0.9403 2.0517 3.3582 1.87E−011.4427 0.1883 0.8882 2.3432 0.9974 2.0867 CCF VSR hCV11758801 1.41370.906 2.2057 1.5378 0.2181 0.8769 2.6969 1.0029 2.3579 UCSF hCV118612550.9991 1.0594 0.8647 1.2979 5.0497 8.01E−02 0.9226 0.0817 0.7474 1.13890.786 1.083 CCF VSR hCV11861255 0.9773 0.8306 0.6583 1.0482 5.75335.63E−02 0.8012 0.0919 0.6322 1.0153 0.669 0.9594 UCSF hCV120719390.8937 0.9289 0.7575 1.1392 6.4 4.08E−02 0.8483 0.0862 0.6794 1.05920.7164 1.0044 CCF VSR hCV12071939 1.5708 0.715 0.561  0.9113 7.41722.45E−02 0.8078 0.1001 0.6243 1.0453 0.664 0.9829 UCSF hCV1209800 0.6399 0.4432 0.9239 0.6215 0.183 0.388 0.9957 0.4342 0.8896 CCF VSRhCV1209800  0.7072 0.462  1.0826 0.6421 0.2097 0.3741 1.012 0.42570.9685 UCSF hCV1262973  3.7788 1.1497 0.8834 1.4962 2.9516 2.29E−011.2188 0.1176 0.9004 1.6498 0.968 1.5346 CCF VSR hCV1262973  2.13771.4832 1.1222 1.9602 7.9944 1.84E−02 1.3186 0.1276 0.9493 1.8315 1.02691.6932 UCSF hCV1348610  1.7582 1.2518 0.9947 1.5753 5.2978 7.07E−021.162 0.0692 0.9724 1.3886 1.0147 1.3307 CCF VSR hCV1348610  1.83131.0083 0.7811 1.3017 5.0887 7.85E−02 1.1644 0.0792 0.9495 1.4278 0.9971.3598 UCSF hCV1408483  1.8681 1.286 1.0429 1.5858 5.472 6.48E−02 1.18660.0905 0.9398 1.4982 0.9937 1.417 CCF VSR hCV1408483  2.263  1.28071.0131 1.619 4.5423 1.03E−01 1.2184 0.0981 0.9464 1.5685 1.0053 1.4766UCSF hCV1452085  1.0993 0.9415 0.7362 1.2039 4.3881 1.11E−01 0.86130.1146 0.6411 1.1571 0.688 1.0783 CCF VSR hCV1452085  2.5937 0.73040.5467 0.9759 4.5378 1.03E−01 0.7814 0.132 0.5562 1.0978 0.6033 1.0121UCSF hCV15851766 0.5279 0.2956 0.9429 0.5338 0.2938 0.2504 1.1379 0.30010.9495 CCF VSR hCV15851766 0.4941 0.2721 0.8972 0.5012 0.3016 0.23051.0901 0.2775 0.9053 UCSF hCV15857769 1.8396 1.0992 0.8971 1.3468 3.13522.09E−01 1.1387 0.0743 0.9404 1.3788 0.9845 1.3172 CCF VSR hCV158577692.2918 0.9801 0.781  1.23 4.4526 1.08E−01 1.1125 0.0859 0.8918 1.3880.9402 1.3165 UCSF hCV15879601 2.2181 0.7379 0.5516 0.9872 5.11157.76E−02 0.7329 0.1392 0.5121 1.0489 0.558 0.9628 CCF VSR hCV158796010.8893 0.6304 1.2545 0.7676 0.1658 0.5008 1.1767 0.5546 1.0624 UCSFhCV16134786 2.23  1.2299 0.9978 1.5159 4.4069 1.10E−01 1.2019 0.08790.9584 1.5073 1.0117 1.4278 CCF VSR hCV16134786 2.0327 1.3513 1.06581.7133 6.1591 4.60E−02 1.2376 0.0991 0.9587 1.5977 1.0191 1.5031 UCSFhCV1619596  1.7527 1.1655 0.9517 1.4273 2.9745 2.26E−01 1.141 0.07620.9377 1.3884 0.9827 1.3248 CCF VSR hCV1619596  2.1107 1.2959 1.032 1.6274 5.6095 6.05E−02 1.2231 0.0898 0.9706 1.5413 1.0258 1.4584 UCSFhCV16336   1.8365 0.7982 0.6189 1.0296 3.2722 1.95E−01 0.8148 0.11590.6045 1.0982 0.6492 1.0226 CCF VSR hCV16336   0.9528 0.7564 0.57171.0007 9.0123 1.10E−02 0.7053 0.1307 0.5037 0.9876 0.5459 0.9113 UCSFhCV1723718  1.8965 1.1481 0.9381 1.4051 3.9209 1.41E−01 1.1566 0.07390.9562 1.399 1.0007 1.3368 CCF VSR hCV1723718  1.8502 1.2585 1.00071.5826 4.2931 1.17E−01 1.1795 0.086 0.9452 1.4719 0.9966 1.396 UCSFhCV1958451  1.1295 0.835 0.6812 1.0236 4.2666 1.18E−01 0.8459 0.08180.6853 1.0442 0.7206 0.9929 CCF VSR hCV1958451  0.948  0.8855 0.70351.1145 5.3527 6.88E−02 0.8225 0.0916 0.6496 1.0413 0.6873 0.9842 UCSFhCV2121658  2.3922 0.7548 0.594  0.959 5.3775 6.80E−02 0.7964 0.110.5999 1.0572 0.642 0.9879 CCF VSR hCV2121658  1.009  0.9012 0.69111.1752 5.1433 7.64E−02 0.8253 0.122 0.6028 1.1299 0.6498 1.0481 UCSFhCV2358247  2.1862 1.3805 1.0441 1.8253 5.9832 5.02E−02 1.2462 0.13270.8855 1.754 0.9609 1.6163 CCF VSR hCV2358247  1.4217 1.0009 2.01941.6023 0.1682 1.0388 2.4713 1.1522 2.2281 UCSF hCV2390937  2.4919 0.78750.5878 1.0551 3.1758 2.04E−01 0.7807 0.14 0.5444 1.1196 0.5934 1.0272CCF VSR hCV2390937  7.7934 0.6756 0.4839 0.9432 5.0842 7.87E−02 0.69460.1622 0.4575 1.0547 0.5055 0.9545 UCSF hCV25473186 1.7391 1.3253 1.05081.6714 6.4292 4.02E−02 1.1555 0.0691 0.9672 1.3806 1.0092 1.3231 CCF VSRhCV25473186 2.0894 1.3927 1.0842 1.789 8.9051 1.16E−02 1.2404 0.07881.0126 1.5194 1.0629 1.4475 UCSF hCV25596936 2.401  1.3229 1.0074 1.73734.7012 9.53E−02 1.2167 0.1296 0.8714 1.6988 0.9438 1.5685 CCF VSRhCV25596936 3.8636 1.5454 1.1505 2.0759 8.4034 1.50E−02 1.4683 0.13521.0364 2.0802 1.1264 1.914 UCSF hCV25615822 1.1906 0.7838 1.8085 1.25670.2061 0.7391 2.1366 0.8391 1.882 CCF VSR hCV25615822 24.49  1.50041.0137 2.2209 3.6716 1.59E−01 1.4756 0.1923 0.8991 2.4217 1.0121 2.1512UCSF hCV25983294 1.4958 0.7576 0.6112 0.9391 6.5483 3.78E−02 0.8190.0911 0.6477 1.0355 0.6851 0.979 CCF VSR hCV25983294 1.2907 0.78230.615  0.9951 4.5596 1.02E−01 0.8136 0.0994 0.6298 1.0509 0.6696 0.9885UCSF hCV2637554  2.1524 1.0848 0.8856 1.3286 6.3881 4.10E−02 1.18050.0745 0.9745 1.4301 1.0202 1.366 CCF VSR hCV2637554 2.0013 1.2089 0.96 1.5224 4.2815 1.18E−01 1.1927 0.0843 0.96 1.4817 1.0111 1.4068 UCSFhCV26478797 1.3378 0.8019 0.6554 0.9812 4.6697 9.68E−02 0.8647 0.08080.7022 1.0647 0.738 1.013 CCF VSR hCV26478797 0.9388 0.9527 0.759 1.1958 5.2035 7.41E−02 0.8558 0.0894 0.6798 1.0773 0.7182 1.0196 UCSFhCV26881276 1.5173 1.198 0.9771 1.4689 3.0209 2.21E−01 1.098 0.0730.9099 1.325 0.9517 1.2667 CCF VSR hCV26881276 2.087  1.1799 0.93391.4906 5.8097 5.48E−02 1.2202 0.0813 0.9896 1.5046 1.0404 1.4311 UCSFhCV27077072 1.1924 0.8208 0.67  1.0055 3.7499 1.53E−01 0.8885 0.07420.7339 1.0756 0.7682 1.0276 CCF VSR hCV27077072 1.072  0.8675 0.68981.0909 3.1285 2.09E−01 0.8634 0.0832 0.6968 1.0698 0.7334 1.0163 UCSFhCV27473671 1.8204 1.169 0.9561 1.4294 3.4061 1.82E−01 1.147 0.07490.9457 1.3912 0.9904 1.3285 CCF VSR hCV27473671 2.4111 1.1634 0.926 1.4617 5.4661 6.50E−02 1.2203 0.0873 0.9746 1.5279 1.0284 1.448 UCSFhCV27494483 4.843  1.3469 0.9846 1.8425 3.554 1.69E−01 1.3368 0.14710.9151 1.9528 1.0019 1.7837 CCF VSR hCV27494483 33.922  1.4595 1.00392.122 4.3507 1.14E−01 1.4827 0.1819 0.928 2.3692 1.038 2.118 UCSFhCV27504565 1.4792 0.7652 0.6244 0.9376 7.0162 3.00E−02 0.8774 0.07980.7144 1.0776 0.7504 1.0256 CCF VSR hCV27504565 0.6227 0.9523 0.7558 1.214.186 8.31E−04 0.7854 0.0962 0.6131 1.0062 0.6505 0.9483 UCSFhCV27511436 0.6798 0.9205 0.7397 1.1455 10.955 4.18E−03 0.808 0.09830.6273 1.0408 0.6664 0.9797 CCF VSR hCV27511436 1.3267 0.8181 0.64021.0455 3.3771 1.85E−01 0.824 0.1046 0.6294 1.0787 0.6713 1.0114 UCSFhCV2769503  1.8479 1.2811 1.0429 1.5738 6.9114 3.16E−02 1.1938 0.07180.9922 1.4364 1.0371 1.3743 CCF VSR hCV2769503  2.1723 1.4676 1.16241.853 11.864 2.65E−03 1.2971 0.0832 1.0469 1.607 1.1019 1.5268 UCSFhCV27892569 2.0397 1.135 0.9281 1.3881 2.8209 2.44E−01 1.1428 0.08010.9298 1.4046 0.9768 1.337 CCF VSR hCV27892569 1.5785 1.277 1.0116 1.6124.3397 1.14E−01 1.1328 0.0923 0.8931 1.4367 0.9453 1.3574 UCSFhCV28036404 0.9867 1.0241 0.8322 1.2603 4.7358 9.37E−02 0.9087 0.08730.7256 1.138 0.7657 1.0784 CCF VSR hCV28036404 1.3363 0.7634 0.60220.9676 5.7808 5.56E−02 0.7897 0.102 0.6072 1.0269 0.6466 0.9644 UCSFhCV2851380  1.1071 0.8341 0.6447 1.0792 5.5293 6.30E−02 0.776 0.11940.5705 1.0555 0.614 0.9807 CCF VSR hCV2851380  1.7468 0.7736 0.58811.0174 3.8106 1.49E−01 0.7859 0.1241 0.5709 1.0819 0.6163 1.0023 UCSFhCV29401764 1.3214 0.7552 0.6161 0.9257 7.6343 2.20E−02 0.8911 0.07460.7354 1.0798 0.7699 1.0313 CCF VSR hCV29401764 1.0456 0.7503 0.59550.9452 6.9627 3.08E−02 0.8152 0.0835 0.6574 1.0109 0.6921 0.9603 UCSFCCF hCV29537898 5.1638 1.1836 0.9169 1.528 4.7982 9.08E−02 1.2655 0.11540.94 1.7036 1.0093 1.5867 VSR hCV29537898 66.901  1.23 0.9105 1.66166.3117 4.26E−02 1.3202 0.1425 0.9147 1.9055 0.9986 1.7455 UCSFhCV29539757 1.1886 0.7331 0.5986 0.8979 9.1106 1.05E−02 0.835 0.07660.6854 1.0172 0.7185 0.9703 CCF VSR hCV29539757 0.9579 0.772 0.6145 0.977.5953 2.24E−02 0.7947 0.0847 0.639 0.9884 0.6732 0.9381 UCSF hCV302629 2.4155 1.0205 0.8322 1.2514 10.938 4.22E−03 1.203 0.075 0.9915 1.45951.0384 1.3936 CCF VSR hCV302629  2.2169 0.951 0.7559 1.1966 4.54061.03E−01 1.1006 0.0868 0.8801 1.3764 0.9284 1.3047 UCSF hCV303082020.9273 0.9368 0.7625 1.151 5.6664 5.88E−02 0.8535 0.0865 0.683 1.06660.7204 1.0113 CCF VSR hCV30308202 1.3882 0.7642 0.6007 0.9721 4.97648.31E−02 0.8199 0.0988 0.6356 1.0575 0.6755 0.9951 UCSF hCV3054550 2.7861 1.1966 0.9619 1.4885 4.0552 1.32E−01 1.2126 0.0944 0.9507 1.54651.0076 1.4592 CCF VSR hCV3054550  1.9825 1.2611 0.9878 1.6101 3.45571.78E−01 1.1702 0.1058 0.8911 1.5368 0.9511 1.4399 UCSF hCV3082219 2.4615 1.2484 0.9921 1.5709 3.4741 1.76E−01 1.1914 0.1045 0.9102 1.55930.9707 1.4621 CCF VSR hCV3082219  4.2435 1.3479 1.0403 1.7465 6.32824.23E−02 1.3418 0.1161 0.995 1.8094 1.0688 1.6846 UCSF hCV311375071.798  1.1779 0.9633 1.4403 3.228 1.99E−01 1.1451 0.0768 0.9396 1.39570.9851 1.3312 CCF VSR hCV31137507 2.0436 1.1512 0.9168 1.4454 2.7242.56E−01 1.1555 0.0873 0.9227 1.447 0.9737 1.3713 UCSF hCV312278489.4209 1.6482 1.1797 2.3027 7.5344 2.31E−02 1.5772 0.1633 1.0357 2.40171.1453 2.172 CCF VSR hCV31227848 25.061  1.7955 1.2252 2.6312 8.01961.81E−02 1.7397 0.1873 1.0738 2.8185 1.2051 2.5114 UCSF hCV315736211.0772 0.8585 0.7027 1.0489 3.9481 1.39E−01 0.8583 0.0781 0.7019 1.04940.7365 1.0001 CCF VSR hCV31573621 0.9627 0.9547 0.7597 1.1997 4.71769.45E−02 0.862 0.0889 0.6855 1.0839 0.7241 1.0261 UCSF hCV317052142.436  1.0888 0.8875 1.3357 5.6238 6.01E−02 1.1819 0.0808 0.9598 1.45531.0087 1.3847 CCF VSR hCV31705214 2.1071 1.36 1.0787 1.7147 7.06762.92E−02 1.2564 0.0936 0.9873 1.5989 1.0459 1.5094 UCSF hCV321607122.3242 1.2959 1.0527 1.5953 6.2375 4.42E−02 1.2364 0.0889 0.9833 1.55461.0387 1.4718 CCF VSR hCV32160712 3.5585 1.141 0.8916 1.4602 4.00861.35E−01 1.2139 0.1059 0.924 1.5948 0.9863 1.4941 UCSF hCV435733  1.76951.2548 1.0241 1.5376 5.6002 6.08E−02 1.1784 0.0736 0.9748 1.4245 1.021.3613 CCF VSR hCV435733  1.347  1.4275 1.1357 1.7943 11.119 3.85E−031.1155 0.0849 0.8964 1.388 0.9445 1.3173 UCSF hCV454333  1.086  0.91360.7266 1.1488 4.1171 1.28E−01 0.8504 0.1038 0.6509 1.1111 0.6938 1.0423CCF VSR hCV454333  0.921  0.7886 0.5993 1.0378 7.7331 2.09E−02 0.72440.1244 0.5257 0.9981 0.5676 0.9245 UCSF hCV540056  43.792  0.6359 0.42230.9575 4.7627 9.24E−02 0.6783 0.2003 0.4049 1.1362 0.4581 1.0044 CCF VSRhCV540056  0.5818 0.3639 0.9302 0.5919 0.2359 0.3224 1.0869 0.37280.9399 UCSF hCV7917138  2.1676 1.2793 1.0412 1.5718 6.4455 3.98E−021.2368 0.0842 0.9956 1.5364 1.0486 1.4587 CCF VSR hCV7917138  3.24541.0272 0.8116 1.3 4.742 9.34E−02 1.1509 0.0975 0.8953 1.4796 0.95071.3933 UCSF hCV8147903  1.0914 0.8028 0.6521 0.9885 6.0203 4.93E−020.8113 0.0854 0.6512 1.0109 0.6863 0.9591 CCF VSR hCV8147903  1.12130.886 0.7007 1.1204 3.0613 2.16E−01 0.85 0.0968 0.6625 1.0905 0.70321.0275 UCSF hCV8754449  1.425  0.8091 0.6607 0.9907 4.2677 1.18E−010.8909 0.0798 0.7253 1.0943 0.7618 1.0418 CCF VSR hCV8754449  0.64950.9676 0.7676 1.2199 13.591 1.12E−03 0.7922 0.0955 0.6195 1.013 0.65710.9552 UCSF hCV8820007  1.0857 1.0262 0.8379 1.2569 2.9617 2.27E−010.9289 0.0813 0.7535 1.1452 0.7922 1.0893 CCF VSR hCV8820007  0.90330.8364 0.662  1.0567 7.1036 2.87E−02 0.7818 0.0931 0.6152 0.9937 0.65150.9383 UCSF hCV8942032  2.4618 1.2231 0.9811 1.5249 3.5479 1.70E−011.1992 0.0965 0.9353 1.5375 0.9925 1.4488 CCF VSR hCV8942032  2.79311.2768 0.9839 1.6567 3.9974 1.36E−01 1.26 0.1132 0.9414 1.6865 1.00931.5729

TABLE 20 GENO- hCV # rs # Gene OUTCOME ADJUST MODE TYPE hCV1958451rs2985822  MIER1 EO_STK AGE MALE GEN GT DIAB HTN hCV1958451 rs2985822 MIER1 EO_STK AGE MALE DOM GT or GG DIAB HTN hCV1958451 rs2985822  MIER1EO_STK GEN GT hCV1958451 rs2985822  MIER1 EO_STK AGE MALE GEN GG DIABHTN hCV1958451 rs2985822  MIER1 LACUNAR_ GEN GT STK hCV27494483rs3748743  SLC22A15 CE_STK GEN TC hCV27494483 rs3748743  SLC22A15 CE_STKDOM TC or TT hCV27494483 rs3748743  SLC22A15 CE_STK ADD T hCV27494483rs3748743  SLC22A15 ISCHEMIC_ DOM TC or TT STK hCV27494483 rs3748743 SLC22A15 ISCHEMIC_ ADD T STK hCV27494483 rs3748743  SLC22A15 ISCHEMIC_GEN TC STK hCV27504565 rs3219489  MUTYH ATHERO_ AGE MALE GEN CG STK DIABHTN hCV27504565 rs3219489  MUTYH ATHERO_ AGE MALE DOM CG or CC STK DIABHTN hCV27504565 rs3219489  MUTYH ATHERO_ AGE MALE GEN CC STK DIAB HTNhCV27504565 rs3219489  MUTYH ATHERO_ GEN CG STK hCV27504565 rs3219489 MUTYH ATHERO_ DOM CG or CC STK hCV27504565 rs3219489  MUTYH ATHERO_ GENCC STK hCV27504565 rs3219489  MUTYH ISCHEMIC_ GEN CG STK hCV27504565rs3219489  MUTYH NOHD_STK GEN CG hCV27504565 rs3219489  MUTYH NOHD_STKAGE MALE GEN CG DIAB HTN hCV27504565 rs3219489  MUTYH NONCE_ AGE MALEGEN CG STK DIAB HTN hCV27504565 rs3219489  MUTYH NONCE_ GEN CG STKhCV27504565 rs3219489  MUTYH RECURRENT_ AGE MALE GEN CG STK DIAB HTNhCV27504565 rs3219489  MUTYH RECURRENT_ AGE MALE DOM CG or CC STK DIABHTN hCV8754449 rs781226  TESK2 ATHERO_ AGE MALE GEN CT STK DIAB HTNhCV8754449 rs781226  TESK2 ATHERO_ AGE MALE DOM CT or CC STK DIAB HTNhCV8754449 rs781226  TESK2 ATHERO_ GEN CT STK hCV8754449 rs781226  TESK2ATHERO_ DOM CT or CC STK hCV8754449 rs781226  TESK2 ATHERO_ GEN CC STKhCV8754449 rs781226  TESK2 ATHERO_ AGE MALE GEN CC STK DIAB HTNhCV8754449 rs781226  TESK2 RECURRENT_ AGE MALE GEN CT STK DIAB HTNhCV8754449 rs781226  TESK2 RECURRENT_ AGE MALE DOM CT or CC STK DIAB HTNhCV2091644 rs1010   VAMP8 CE_STK REC CC hCV8820007 rs938390  ATHERO GENTA STK hCV8820007 rs938390  ISCHEMIC_ GEN TA STK hCV8820007 rs938390 ISCHEMIC_ AGE MALE GEN TA STK DIAB HTN hCV8820007 rs938390  NOHD_STK GENTA hCV8820007 rs938390  NOHD_STK AGE MALE GEN TA DIAB HTN hCV8820007rs938390  NOHD_STK AGE MALE DOM TA or TT DIAB HTN hCV8820007 rs938390 NOHD_STK DOM TA or TT hCV11354788 rs12644625 LOC729065 ATHERO_ AGE MALEADD T STK DIAB HTN hCV11354788 rs12644625 LOC729065 ATHERO_ AGE MALE DOMTC or TT STK DIAB HTN hCV11354788 rs12644625 LOC729065 ATHERO_ AGE MALEGEN TC STK DIAB HTN hCV11354788 rs12644625 LOC729065 ATHERO_ DOM TC orTT STK hCV11354788 rs12644625 LOC729065 ATHERO_ GEN TC STK hCV11354788rs12644625 LOC729065 ATHERO_ ADD T STK hCV11354788 rs12644625 LOC729065CE_STK ADD T hCV11354788 rs12644625 LOC729065 CE_STK DOM TC or TThCV11354788 rs12644625 LOC729065 CE_STK AGE MALE ADD T DIAB HTNhCV11354788 rs12644625 LOC729065 CE_STK AGE MALE DOM TC or TT DIAB HTNhCV11354788 rs12644625 LOC729065 CE_STK GEN TC hCV11354788 rs12644625LOC729065 CE_STK AGE MALE GEN TC DIAB HTN hCV11354788 rs12644625LOC729065 CE_STK GEN TT hCV11354788 rs12644625 LOC729065 CE_STK REC TThCV11354788 rs12644625 LOC729065 CE_STK AGE MALE GEN TT DIAB HTNhCV11354788 rs12644625 LOC729065 EO_STK AGE MALE ADD T DIAB HTNhCV11354788 rs12644625 LOC729065 EO_STK DOM TC or TT hCV11354788rs12644625 LOC729065 EO_STK ADD T hCV11354788 rs12644625 LOC729065EO_STK AGE MALE DOM TC or TT DIAB HTN hCV11354788 rs12644625 LOC729065EO_STK GEN TC hCV11354788 rs12644625 LOC729065 EO_STK AGE MALE GEN TCDIAB HTN hCV11354788 rs12644625 LOC729065 ISCHEMIC_ DOM TC or TT STKhCV11354788 rs12644625 LOC729065 ISCHEMIC_ ADD T STK hCV11354788rs12644625 LOC729065 ISCHEMIC_ GEN TC STK hCV11354788 rs12644625LOC729065 ISCHEMIC_ AGE MALE ADD T STK DIAB HTN hCV11354788 rs12644625LOC729065 ISCHEMIC_ AGE MALE DOM TC or TT STK DIAB HTN hCV11354788rs12644625 LOC729065 ISCHEMIC_ AGE MALE GEN TC STK DIAB HTN hCV11354788rs12644625 LOC729065 NOHD_STK ADD T hCV11354788 rs12644625 LOC729065NOHD_STK DOM TC or TT hCV11354788 rs12644625 LOC729065 NOHD_STK GEN TChCV11354788 rs12644625 LOC729065 NOHD_STK AGE MALE ADD T DIAB HTNhCV11354788 rs12644625 LOC729065 NOHD_STK AGE MALE DOM TC or TT DIAB HTNhCV11354788 rs12644625 LOC729065 NOHD_STK AGE MALE GEN TC DIAB HTNhCV11354788 rs12644625 LOC729065 NONCE_ GEN TC STK hCV11354788rs12644625 LOC729065 NONCE_ DOM TC or TT STK hCV11354788 rs12644625LOC729065 NONCE_ AGE MALE DOM TC or TT STK DIAB HTN hCV11354788rs12644625 LOC729065 RECURRENT_ AGE MALE GEN TC STK DIAB HTN hCV11354788rs12644625 LOC729065 RECURRENT_ AGE MALE DOM TC or TT STK DIAB HTNhCV11354788 rs12644625 LOC729065 RECURRENT_ AGE MALE ADD T STK DIAB HTNhCV11354788 rs12644625 LOC729065 RECURRENT_ DOM TC or TT STK hCV11354788rs12644625 LOC729065 RECURRENT_ GEN TC STK hCV11354788 rs12644625LOC729065 RECURRENT_ ADD T STK hCV16158671 rs2200733  ATHERO_ AGE MALEADD T STK DIAB HTN hCV16158671 rs2200733  ATHERO_ AGE MALE DOM TC or TTSTK DIAB HTN hCV16158671 rs2200733  ATHERO_ DOM TC or TT STK hCV16158671rs2200733  ATHERO_ ADD T STK hCV16158671 rs2200733  ATHERO_ GEN TC STKhCV16158671 rs2200733  ATHERO_ AGE MALE GEN TC STK DIAB HTN hCV16158671rs2200733  CE_STK ADD T hCV16158671 rs2200733  CE_STK DOM TC or TThCV16158671 rs2200733  CE_STK GEN TC hCV16158671 rs2200733  CE_STK AGEMALE ADD T DIAB HTN hCV16158671 rs2200733  CE_STK AGE MALE DOM TC or TTDIAB HTN hCV16158671 rs2200733  CE_STK AGE MALE GEN TC DIAB HTNhCV16158671 rs2200733  CE_STK GEN TT hCV16158671 rs2200733  CE_STK RECTT hCV16158671 rs2200733  CE_STK AGE MALE GEN TT DIAB HTN hCV16158671rs2200733  EO_STK DOM TC or TT hCV16158671 rs2200733  EO_STK ADD ThCV16158671 rs2200733  EO_STK AGE MALE ADD T DIAB HTN hCV16158671rs2200733  EO_STK GEN TC hCV16158671 rs2200733  EO_STK AGE MALE DOM TCor TT DIAB HTN hCV16158671 rs2200733  EO_STK AGE MALE GEN TC DIAB HTNhCV16158671 rs2200733  ISCHEMIC_ DOM TC or TT STK hCV16158671 rs2200733 ISCHEMIC_ ADD T STK hCV16158671 rs2200733  ISCHEMIC_ GEN TC STKhCV16158671 rs2200733  ISCHEMIC_ AGE MALE ADD T STK DIAB HTN hCV16158671rs2200733  ISCHEMIC_ AGE MALE DOM TC or TT STK DIAB HTN hCV16158671rs2200733  ISCHEMIC_ AGE MALE GEN TC STK DIAB HTN hCV16158671 rs2200733 NOHD_STK ADD T hCV16158671 rs2200733  NOHD_STK DOM TC or TT hCV16158671rs2200733  NOHD_STK GEN TC hCV16158671 rs2200733  NOHD_STK AGE MALE ADDT DIAB HTN hCV16158671 rs2200733  NOHD_STK AGE MALE DOM TC or TT DIABHTN hCV16158671 rs2200733  NOHD_STK AGE MALE GEN TC DIAB HTN hCV16158671rs2200733  NOHD_STK AGE MALE GEN TT DIAB HTN hCV16158671 rs2200733 NONCE_ DOM TC or TT STK hCV16158671 rs2200733  NONCE_ GEN TC STKhCV16158671 rs2200733  NONCE_ ADD T STK hCV16158671 rs2200733  NONCE_AGE MALE ADD T STK DIAB HTN hCV16158671 rs2200733  NONCE_ AGE MALE DOMTC or TT STK DIAB HTN hCV16158671 rs2200733  RECURRENT_ AGE MALE GEN TCSTK DIAB HTN hCV16158671 rs2200733  RECURRENT_ AGE MALE DOM TC or TT STKDIAB HTN hCV16158671 rs2200733  RECURRENT_ AGE MALE ADD T STK DIAB HTNhCV16158671 rs2200733  RECURRENT_ DOM TC or TT STK hCV16158671rs2200733  RECURRENT_ GEN TC STK hCV16158671 rs2200733  RECURRENT_ ADD TSTK hCV16336 rs362277  HD ATHERO_ REC CC STK hCV16336 rs362277  HDATHERO_ ADD C STK hCV16336 rs362277  HD ATHERO_ AGE MALE REC CC STK DIABHTN hCV16336 rs362277  HD CE_STK ADD C hCV16336 rs362277  HD CE_STK RECCC hCV16336 rs362277  HD CE_STK AGE MALE ADD C DIAB HTN hCV16336rs362277  HD CE_STK AGE MALE REC CC DIAB HTN hCV16336 rs362277  HDCE_STK GEN CC hCV16336 rs362277  HD EO_STK AGE MALE REC CC DIAB HTNhCV16336 rs362277  HD EO_STK AGE MALE ADD C DIAB HTN hCV16336 rs362277 HD EO_STK REC CC hCV16336 rs362277  HD EO_STK ADD C hCV16336 rs362277 HD ISCHEMIC_ ADD C STK hCV16336 rs362277  HD ISCHEMIC_ REC CC STKhCV16336 rs362277  HD ISCHEMIC_ AGE MALE ADD C STK DIAB HTN hCV16336rs362277  HD ISCHEMIC_ AGE MALE REC CC STK DIAB HTN hCV16336 rs362277 HD NOHD_STK ADD C hCV16336 rs362277  HD NOHD_STK REC CC hCV16336rs362277  HD NONCE_ REC CC STK hCV16336 rs362277  HD NONCE_ ADD C STKhCV16336 rs362277  HD NONCE_ AGE MALE REC CC STK DIAB HTN hCV16336rs362277  HD NONCE_ AGE MALE ADD C STK DIAB HTN hCV26478797 rs2015018 CHSY-2 CE_STK REC GG hCV11425801 rs3805953  PEX6 ATHERO_ AGE MALE GEN CTSTK DIAB HTN hCV11425801 rs3805953  PEX6 ATHERO_ AGE MALE DOM CT or CCSTK DIAB HTN hCV11425801 rs3805953  PEX6 ATHERO_ GEN CT STK hCV11425801rs3805953  PEX6 ATHERO_ DOM CT or CC STK hCV11425801 rs3805953  PEX6ATHERO_ ADD C STK hCV11425801 rs3805953  PEX6 ATHERO_ GEN CC STKhCV11425801 rs3805953  PEX6 ATHERO_ AGE MALE ADD C STK DIAB HTNhCV11425801 rs3805953  PEX6 EO_STK GEN CT hCV11425801 rs3805953  PEX6EO_STK AGE MALE GEN CT DIAB HTN hCV11425801 rs3805953  PEX6 EO_STK DOMCT or CC hCV11425801 rs3805953  PEX6 EO_STK AGE MALE DOM CT or CC DIABHTN hCV11425801 rs3805953  PEX6 ISCHEMIC_ AGE MALE GEN CT STK DIAB HTNhCV11425801 rs3805953  PEX6 ISCHEMIC_ AGE MALE DOM CT or CC STK DIAB HTNhCV11425801 rs3805953  PEX6 ISCHEMIC_ GEN CT STK hCV11425801 rs3805953 PEX6 ISCHEMIC_ DOM CT or CC STK hCV11425801 rs3805953  PEX6 ISCHEMIC_ADD C STK hCV11425801 rs3805953  PEX6 LACUNAR_ AGE MALE GEN CT STK DIABHTN hCV11425801 rs3805953  PEX6 LACUNAR_ AGE MALE DOM CT or CC STK DIABHTN hCV11425801 rs3805953  PEX6 LACUNAR_ GEN CT STK hCV11425801rs3805953  PEX6 NOHD_STK AGE MALE GEN CT DIAB HTN hCV11425801 rs3805953 PEX6 NOHD_STK AGE MALE DOM CT or CC DIAB HTN hCV11425801 rs3805953  PEX6NOHD_STK DOM CT or CC hCV11425801 rs3805953  PEX6 NOHD_STK GEN CThCV11425801 rs3805953  PEX6 NOHD_STK ADD C hCV11425801 rs3805953  PEX6NOHD_STK GEN CC hCV11425801 rs3805953  PEX6 NONCE_ AGE MALE DOM CT or CCSTK DIAB HTN hCV11425801 rs3805953  PEX6 NONCE_ GEN CT STK hCV11425801rs3805953  PEX6 NONCE_ DOM CT or CC STK hCV11425801 rs3805953  PEX6NONCE_ ADD C STK hCV11425801 rs3805953  PEX6 NONCE_ GEN CC STKhCV11425801 rs3805953  PEX6 RECURRENT_ AGE MALE GEN CT STK DIAB HTNhCV11425801 rs3805953  PEX6 RECURRENT_ GEN CT STK hCV11425842 rs10948059GNMT ATHERO_ AGE MALE DOM CT or CC STK DIAB HTN hCV11425842 rs10948059GNMT ATHERO_ AGE MALE GEN CT STK DIAB HTN hCV11425842 rs10948059 GNMTATHERO_ DOM CT or CC STK hCV11425842 rs10948059 GNMT ATHERO_ AGE MALEGEN CC STK DIAB HTN hCV11425842 rs10948059 GNMT ATHERO_ GEN CT STKhCV11425842 rs10948059 GNMT EO_STK GEN CT hCV11425842 rs10948059 GNMTEO_STK DOM CT or CC hCV11425842 rs10948059 GNMT EO_STK AGE MALE GEN CTDIAB HTN hCV11425842 rs10948059 GNMT EO_STK AGE MALE DOM CT or CC DIABHTN hCV11425842 rs10948059 GNMT EO_STK GEN CC hCV11425842 rs10948059GNMT ISCHEMIC_ AGE MALE GEN CT STK DIAB HTN hCV11425842 rs10948059 GNMTISCHEMIC_ AGE MALE DOM CT or CC STK DIAB HTN hCV11425842 rs10948059 GNMTNONCE_ AGE MALE GEN CT STK DIAB HTN hCV11425842 rs10948059 GNMT NONCE_AGE MALE DOM CT or CC STK DIAB HTN hCV1209800 rs35067690 CLIC5 CE_STKREC GG hCV1209800 rs35067690 CLIC5 CE STK ADD G hCV16134786 rs2857595 EO_STK ADD A hCV16134786 rs2857595  EO_STK GEN AA hCV16134786 rs2857595 EO_STK REC AA hCV16134786 rs2857595  EO_STK DOM AG or AA hCV16134786rs2857595  LACUNAR_ GEN AA STK hCV16134786 rs2857595  LACUNAR_ REC AASTK hCV16134786 rs2857595  LACUNAR_ ADD A STK hCV16134786 rs2857595 NONCE_ ADD A STK hCV16134786 rs2857595  NONCE_ GEN AA STK hCV25651109rs35690712 SLC39A7 ISCHEMIC_ GEN GG STK hCV25651109 rs35690712 SLC39A7ISCHEMIC_ DOM GC or GG STK hCV25651109 rs35690712 SLC39A7 ISCHEMIC_ GENGC STK hCV25651109 rs35690712 SLC39A7 NOHD_STK GEN GC hCV25651109rs35690712 SLC39A7 NOHD_STK DOM GC or GG hCV25651109 rs35690712 SLC39A7NOHD_STK GEN GG hCV30308202 rs9482985  LAMA2 RECURRENT_ ADD G STKhCV30308202 rs9482985  LAMA2 RECURRENT_ AGE MALE GEN GG STK DIAB HTNhCV30308202 rs9482985  LAMA2 RECURRENT_ AGE MALE DOM GC or GG STK DIABHTN hCV30308202 rs9482985  LAMA2 RECURRENT_ REC GG STK hCV30308202rs9482985  LAMA2 RECURRENT_ AGE MALE GEN GC STK DIAB HTN hCV30308202rs9482985  LAMA2 RECURRENT_ GEN GG STK hCV3082219 rs1884833  RFXDC1EO_STK ADD A hCV3082219 rs1884833  RFXDC1 LACUNAR_ ADD A STK hCV3082219rs1884833  RFXDC1 LACUNAR_ DOM AG or AA STK hCV3082219 rs1884833  RFXDC1LACUNAR_ GEN AG STK hCV3082219 rs1884833  RFXDC1 NONCE_ ADD A STKhCV3082219 rs1884833  RFXDC1 NONCE_ DOM AG or AA STK hCV3082219rs1884833  RFXDC1 NONCE_ GEN AG STK hCV8942032 rs1264352  DDR1 EO_STKDOM CG or CC hCV8942032 rs1264352  DDR1 EO_STK GEN CG hCV8942032rs1264352  DDR1 EO_STK ADD C hCV8942032 rs1264352  DDR1 EO_STK AGE MALEGEN CG DIAB HTN hCV8942032 rs1264352  DDR1 EO_STK AGE MALE DOM CG or CCDIAB HTN hCV8942032 rs1264352  DDR1 EO_STK AGE MALE ADD C DIAB HTNhCV8942032 rs1264352  DDR1 ISCHEMIC_ AGE MALE GEN CG STK DIAB HTNhCV8942032 rs1264352  DDR1 ISCHEMIC_ AGE MALE DOM CG or CC STK DIAB HTNhCV8942032 rs1264352  DDR1 ISCHEMIC_ AGE MALE ADD C STK DIAB HTNhCV8942032 rs1264352  DDR1 ISCHEMIC_ GEN CG STK hCV8942032 rs1264352 DDR1 ISCHEMIC_ DOM CG or CC STK hCV8942032 rs1264352  DDR1 LACUNAR_ AGEMALE DOM CG or CC STK DIAB HTN hCV8942032 rs1264352  DDR1 LACUNAR_ AGEMALE ADD C STK DIAB HTN hCV8942032 rs1264352  DDR1 LACUNAR_ AGE MALE GENCG STK DIAB HTN hCV8942032 rs1264352  DDR1 LACUNAR_ DOM CG or CC STKhCV8942032 rs1264352  DDR1 LACUNAR_ ADD C STK hCV8942032 rs1264352  DDR1LACUNAR_ GEN CG STK hCV8942032 rs1264352  DDR1 NOHD_STK AGE MALE GEN CGDIAB HTN hCV8942032 rs1264352  DDR1 NOHD_STK AGE MALE DOM CG or CC DIABHTN hCV8942032 rs1264352  DDR1 NOHD_STK GEN CG hCV8942032 rs1264352 DDR1 NONCE_ AGE MALE GEN CG STK DIAB HTN hCV8942032 rs1264352  DDR1NONCE_ AGE MALE DOM CG or CC STK DIAB HTN hCV8942032 rs1264352  DDR1NONCE_ GEN CG STK hCV8942032 rs1264352  DDR1 NONCE_ AGE MALE ADD C STKDIAB HTN hCV8942032 rs1264352  DDR1 NONCE_ DOM CG or CC STK hCV8942032rs1264352  DDR1 RECURRENT_ AGE MALE DOM CG or CC STK DIAB HTN hCV8942032rs1264352  DDR1 RECURRENT_ AGE MALE GEN CG STK DIAB HTN hCV8942032rs1264352  DDR1 RECURRENT_ AGE MALE ADD C STK DIAB HTN hCV8942032rs1264352  DDR1 RECURRENT_ GEN CG STK hCV8942032 rs1264352  DDR1RECURRENT_ DOM CG or CC STK hCV8942032 rs1264352  DDR1 RECURRENT_ ADD CSTK hCV25596936 rs6967117  EPHA1 ATHERO_ GEN TC STK hCV25596936rs6967117  EPHA1 ATHERO_ DOM TC or TT STK hCV25596936 rs6967117  EPHA1ISCHEMIC_ GEN TC STK hCV25596936 rs6967117  EPHA1 LACUNAR_ GEN TC STKhCV25596936 rs6967117  EPHA1 NOHD_STK GEN TC hCV25596936 rs6967117 EPHA1 NONCE_ GEN TC STK hCV25596936 rs6967117  EPHA1 NONCE_ DOM TC or TTSTK hCV25596936 rs6967117  EPHA1 NONCE_ ADD T STK hCV27511436 rs3750145 FZD1 ATHERO_ GEN TC STK hCV27511436 rs3750145  FZD1 ATHERO_ AGE MALE GENTC STK DIAB HTN hCV27511436 rs3750145  FZD1 ATHERO_ DOM TC or TT STKhCV27511436 rs3750145  FZD1 ATHERO_ GEN TT STK hCV27511436 rs3750145 FZD1 ATHERO_ AGE MALE DOM TC or TT STK DIAB HTN hCV27511436 rs3750145 FZD1 ATHERO_ AGE MALE GEN TT STK DIAB HTN hCV27511436 rs3750145  FZD1 CESTK GEN TC hCV27511436 rs3750145  FZD1 CE STK AGE MALE GEN TC DIAB HTNhCV27511436 rs3750145  FZD1 CE_STK AGE MALE DOM TC or TT DIAB HTNhCV27511436 rs3750145  FZD1 CE STK AGE MALE GEN TT DIAB HTN hCV27511436rs3750145  FZD1 CE STK DOM TC or TT hCV27511436 rs3750145  FZD1 EO_STKGEN TC hCV27511436 rs3750145  FZD1 EO_STK DOM TC or TT hCV27511436rs3750145  FZD1 EO_STK AGE MALE GEN TC DIAB HTN hCV27511436 rs3750145 FZD1 EO_STK GEN TT hCV27511436 rs3750145  FZD1 EO_STK AGE MALE DOM TC orTT DIAB HTN hCV27511436 rs3750145  FZD1 EO_STK AGE MALE GEN TT DIAB HTNhCV27511436 rs3750145  FZD1 ISCHEMIC_ AGE MALE GEN TC STK DIAB HTNhCV27511436 rs3750145  FZD1 ISCHEMIC_ DOM TC or TT STK hCV27511436rs3750145  FZD1 ISCHEMIC_ AGE MALE DOM TC or TT STK DIAB HTN hCV27511436rs3750145  FZD1 ISCHEMIC_ AGE MALE GEN TT STK DIAB HTN hCV27511436rs3750145  FZD1 ISCHEMIC_ GEN TT STK hCV27511436 rs3750145  FZD1LACUNAR_ AGE MALE GEN TC STK DIAB HTN hCV27511436 rs3750145  FZD1LACUNAR_ GEN TC STK hCV27511436 rs3750145  FZD1 LACUNAR_ AGE MALE DOM TCor TT STK DIAB HTN hCV27511436 rs3750145  FZD1 LACUNAR_ AGE MALE GEN TTSTK DIAB HTN hCV27511436 rs3750145  FZD1 LACUNAR_ DOM TC or TT STKhCV27511436 rs3750145  FZD1 LACUNAR_ GEN TT STK hCV27511436 rs3750145 FZD1 NOHD_STK GEN TC hCV27511436 rs3750145  FZD1 NOHD_STK AGE MALE GENTC DIAB HTN hCV27511436 rs3750145  FZD1 NOHD_STK DOM TC or TThCV27511436 rs3750145  FZD1 NOHD_STK AGE MALE DOM TC or TT DIAB HTNhCV27511436 rs3750145  FZD1 NOHD_STK AGE MALE GEN TT DIAB HTNhCV27511436 rs3750145  FZD1 NOHD_STK GEN TT hCV27511436 rs3750145  FZD1NONCE_ AGE MALE GEN TC STK DIAB HTN hCV27511436 rs3750145  FZD1 NONCE_DOM TC or TT STK hCV27511436 rs3750145  FZD1 NONCE_ GEN TT STKhCV27511436 rs3750145  FZD1 NONCE_ AGE MALE DOM TC or TT STK DIAB HTNhCV27511436 rs3750145  FZD1 NONCE_ AGE MALE GEN TT STK DIAB HTNhCV29401764 rs7793552  LOC646588 ATHERO_ AGE MALE GEN CT STK DIAB HTNhCV15857769 rs2924914  ATHERO_ ADD T STK hCV15857769 rs2924914  ATHERO_DOM TC or TT STK hCV15857769 rs2924914  ATHERO_ GEN TC STK hCV15857769rs2924914  ATHERO_ AGE MALE GEN TT STK DIAB HTN hCV15857769 rs2924914 ATHERO_ GEN TT STK hCV15857769 rs2924914  CE_STK GEN TC hCV15857769rs2924914  CE_STK DOM TC or TT hCV15857769 rs2924914  ISCHEMIC_ GEN TCSTK hCV15857769 rs2924914  ISCHEMIC_ DOM TC or TT STK hCV15857769rs2924914  ISCHEMIC_ ADD T STK hCV15857769 rs2924914  NOHD_STK GEN TChCV15857769 rs2924914  NOHD_STK DOM TC or TT hCV15857769 rs2924914 NONCE_ DOM TC or TT STK hCV15857769 rs2924914  NONCE_ GEN TC STKhCV15857769 rs2924914  NONCE_ ADD T STK hCV15857769 rs2924914 RECURRENT_ GEN TC STK hCV15857769 rs2924914  RECURRENT_ DOM TC or TT STKhCV15857769 rs2924914  RECURRENT_ AGE MALE GEN TC STK DIAB HTNhCV15857769 rs2924914  RECURRENT_ AGE MALE DOM TC or TT STK DIAB HTNhCV15857769 rs2924914  RECURRENT_ ADD T STK hCV29539757 rs10110659 KCNQ3NONCE_ GEN CA STK hCV1348610 rs3739636  C9orf46 ISCHEMIC_ AGE MALE GENAG STK DIAB HTN hCV1348610 rs3739636  C9orf46 ISCHEMIC_ AGE MALE DOM AGor AA STK DIAB HTN hCV1348610 rs3739636  C9orf46 NOHD_STK AGE MALE GENAG DIAB HTN hCV1348610 rs3739636  C9orf46 NONCE_ AGE MALE GEN AG STKDIAB HTN hCV26505812 rs10757274 C9P21 ATHERO_ AGE MALE REC GG STK DIABHTN hCV26505812 rs10757274 C9P21 NONCE_ AGE MALE REC GG STK DIAB HTNhCV2169762 rs1804689  HPS1 CE_STK GEN TG hCV2169762 rs1804689  HPS1CE_STK DOM TG or TT hCV2169762 rs1804689  HPS1 CE_STK ADD T hCV2169762rs1804689  HPS1 CE_STK AGE MALE DOM TG or TT DIAB HTN hCV2169762rs1804689  HPS1 CE_STK AGE MALE GEN TG DIAB HTN hCV2169762 rs1804689 HPS1 CE_STK AGE MALE ADD T DIAB HTN hCV2169762 rs1804689  HPS1 EO_STKAGE MALE REC TT DIAB HTN hCV2169762 rs1804689  HPS1 ISCHEMIC_ AGE MALEADD T STK DIAB HTN hCV2169762 rs1804689  HPS1 ISCHEMIC_ DOM TG or TT STKhCV2169762 rs1804689  HPS1 ISCHEMIC_ AGE MALE DOM TG or TT STK DIAB HTNhCV2169762 rs1804689  HPS1 ISCHEMIC_ GEN TG STK hCV2169762 rs1804689 HPS1 ISCHEMIC_ AGE MALE GEN TT STK DIAB HTN hCV2169762 rs1804689  HPS1ISCHEMIC_ ADD T STK hCV2169762 rs1804689  HPS1 ISCHEMIC_ AGE MALE GEN TGSTK DIAB HTN hCV2169762 rs1804689  HPS1 ISCHEMIC_ AGE MALE REC TT STKDIAB HTN hCV2169762 rs1804689  HPS1 LACUNAR_ AGE MALE DOM TG or TT STKDIAB HTN hCV2169762 rs1804689  HPS1 NOHD_STK DOM TG or TT hCV2169762rs1804689  HPS1 NOHD_STK GEN TG hCV2169762 rs1804689  HPS1 NOHD_STK ADDT hCV2169762 rs1804689  HPS1 NOHD_STK AGE MALE ADD T DIAB HTN hCV2169762rs1804689  HPS1 NOHD_STK AGE MALE DOM TG or TT DIAB HTN hCV2169762rs1804689  HPS1 NOHD_STK AGE MALE GEN TG DIAB HTN hCV2169762 rs1804689 HPS1 NOHD_STK AGE MALE GEN TT DIAB HTN hCV2169762 rs1804689  HPS1NOHD_STK GEN TT hCV2169762 rs1804689  HPS1 NONCE_ AGE MALE GEN TT STKDIAB HTN hCV2169762 rs1804689  HPS1 NONCE_ AGE MALE ADD T STK DIAB HTNhCV2169762 rs1804689  HPS1 NONCE_ AGE MALE REC TT STK DIAB HTNhCV27830265 rs12762303 ALOX5 ATHERO_ GEN GG STK hCV27830265 rs12762303ALOX5 ATHERO_ REC GG STK hCV27830265 rs12762303 ALOX5 ATHERO_ AGE MALEADD G STK DIAB HTN hCV27830265 rs12762303 ALOX5 ATHERO_ ADD G STKhCV27830265 rs12762303 ALOX5 ATHERO_ AGE MALE GEN GG STK DIAB HTNhCV27830265 rs12762303 ALOX5 ATHERO_ AGE MALE REC GG STK DIAB HTNhCV27830265 rs12762303 ALOX5 ATHERO_ AGE MALE DOM GA or GG STK DIAB HTNhCV27830265 rs12762303 ALOX5 EO_STK AGE MALE ADD G DIAB HTN hCV27830265rs12762303 ALOX5 EO_STK AGE MALE DOM GA or GG DIAB HTN hCV27830265rs12762303 ALOX5 EO_STK AGE MALE GEN GA DIAB HTN hCV27830265 rs12762303ALOX5 ISCHEMIC_ GEN GG STK hCV27830265 rs12762303 ALOX5 ISCHEMIC_ REC GGSTK hCV27830265 rs12762303 ALOX5 ISCHEMIC_ AGE MALE ADD G STK DIAB HTNhCV27830265 rs12762303 ALOX5 ISCHEMIC_ AGE MALE GEN GG STK DIAB HTNhCV27830265 rs12762303 ALOX5 ISCHEMIC_ AGE MALE REC GG STK DIAB HTNhCV27830265 rs12762303 ALOX5 ISCHEMIC_ ADD G STK hCV27830265 rs12762303ALOX5 LACUNAR_ AGE MALE ADD G STK DIAB HTN hCV27830265 rs12762303 ALOX5LACUNAR_ AGE MALE DOM GA or GG STK DIAB HTN hCV27830265 rs12762303 ALOX5NOHD_STK GEN GG hCV27830265 rs12762303 ALOX5 NOHD_STK REC GG hCV27830265rs12762303 ALOX5 NOHD_STK AGE MALE ADD G DIAB HTN hCV27830265 rs12762303ALOX5 NONCE_ AGE MALE ADD G STK DIAB HTN hCV27830265 rs12762303 ALOX5NONCE_ GEN GG STK hCV27830265 rs12762303 ALOX5 NONCE_ ADD G STKhCV27830265 rs12762303 ALOX5 NONCE_ REC GG STK hCV27830265 rs12762303ALOX5 NONCE_ AGE MALE DOM GA or GG STK DIAB HTN hCV27830265 rs12762303ALOX5 NONCE_ AGE MALE GEN GA STK DIAB HTN hCV27830265 rs12762303 ALOX5NONCE_ DOM GA or GG STK hCV27830265 rs12762303 ALOX5 NONCE_ AGE MALE GENGG STK DIAB HTN hCV27830265 rs12762303 ALOX5 RECURRENT_ REC GG STKhCV27830265 rs12762303 ALOX5 RECURRENT_ GEN GG STK hCV27830265rs12762303 ALOX5 RECURRENT_ AGE MALE REC GG STK DIAB HTN hCV27830265rs12762303 ALOX5 RECURRENT_ AGE MALE GEN GG STK DIAB HTN hCV1053082rs544115  NEU3 ATHERO_ AGE MALE DOM CT or CC STK DIAB HTN hCV1053082rs544115  NEU3 ATHERO_ AGE MALE GEN CC STK DIAB HTN hCV1053082 rs544115 NEU3 ATHERO_ AGE MALE GEN CT STK DIAB HTN hCV1053082 rs544115  NEU3CE_STK AGE MALE GEN CC DIAB HTN hCV1053082 rs544115  NEU3 CE_STK AGEMALE DOM CT or CC DIAB HTN hCV1053082 rs544115  NEU3 CE_STK ADD ChCV1053082 rs544115  NEU3 CE_STK AGE MALE GEN CT DIAB HTN hCV1053082rs544115  NEU3 CE_STK REC CC hCV1053082 rs544115  NEU3 EO_STK DOM CT orCC hCV1053082 rs544115  NEU3 EO_STK GEN CC hCV1053082 rs544115  NEU3EO_STK GEN CT hCV1053082 rs544115  NEU3 EO_STK AGE MALE ADD C DIAB HTNhCV1053082 rs544115  NEU3 EO_STK AGE MALE GEN CC DIAB HTN hCV1053082rs544115  NEU3 EO_STK AGE MALE REC CC DIAB HTN hCV1053082 rs544115  NEU3ISCHEMIC_ AGE MALE DOM CT or CC STK DIAB HTN hCV1053082 rs544115  NEU3ISCHEMIC_ AGE MALE GEN CC STK DIAB HTN hCV1053082 rs544115  NEU3ISCHEMIC_ AGE MALE GEN CT STK DIAB HTN hCV1053082 rs544115  NEU3ISCHEMIC_ GEN CC STK hCV1053082 rs544115  NEU3 ISCHEMIC_ DOM CT or CCSTK hCV1053082 rs544115  NEU3 ISCHEMIC_ GEN CT STK hCV1053082 rs544115 NEU3 ISCHEMIC_ ADD C STK hCV1053082 rs544115  NEU3 NOHD_STK AGE MALE DOMCT or CC DIAB HTN hCV1053082 rs544115  NEU3 NOHD_STK AGE MALE GEN CTDIAB HTN hCV1053082 rs544115  NEU3 NOHD_STK AGE MALE GEN CC DIAB HTNhCV1053082 rs544115  NEU3 NOHD_STK GEN CC hCV1053082 rs544115  NEU3NOHD_STK DOM CT or CC hCV1053082 rs544115  NEU3 NOHD_STK GEN CThCV1053082 rs544115  NEU3 NONCE_ AGE MALE DOM CT or CC STK DIAB HTNhCV1053082 rs544115  NEU3 NONCE_ AGE MALE GEN CT STK DIAB HTN hCV1053082rs544115  NEU3 NONCE_ AGE MALE GEN CC STK DIAB HTN hCV1053082 rs544115 NEU3 NONCE_ DOM CT or CC STK hCV1053082 rs544115  NEU3 NONCE_ GEN CC STKhCV1053082 rs544115  NEU3 NONCE_ GEN CT STK hCV1452085 rs12223005 TRIM22ISCHEMIC_ AGE MALE GEN CA STK DIAB HTN hCV1452085 rs12223005 TRIM22LACUNAR_ AGE MALE GEN CA STK DIAB HTN hCV1452085 rs12223005 TRIM22NOHD_STK AGE MALE GEN CA DIAB HTN hCV1452085 rs12223005 TRIM22 NOHD_STKAGE MALE DOM CA or CC DIAB HTN hCV1452085 rs12223005 TRIM22 NOHD_STK AGEMALE GEN CC DIAB HTN hCV1452085 rs12223005 TRIM22 NONCE_ AGE MALE GEN CASTK DIAB HTN hCV1452085 rs12223005 TRIM22 RECURRENT_ AGE MALE GEN CA STKDIAB HTN hCV302629 rs9284183  UBAC2 EO_STK GEN GA hCV11474611 rs3814843 CALM1 ATHERO_ GEN GT STK hCV11474611 rs3814843  CALM1 CE_STK AGE MALEGEN GG DIAB HTN hCV11474611 rs3814843  CALM1 CE_STK AGE MALE REC GG DIABHTN hCV1262973 rs229653  PLEKHG3 CE_STK GEN AG hCV27892569 rs4903741 NRXN3 CE_STK GEN CC hCV27892569 rs4903741  NRXN3 CE_STK REC CChCV27892569 rs4903741  NRXN3 CE_STK ADD C hCV27892569 rs4903741  NRXN3NOHD_STK ADD C hCV27077072 rs8060368  RECURRENT_ ADD C STK hCV27077072rs8060368  RECURRENT_ REC CC STK hCV27077072 rs8060368  RECURRENT_ AGEMALE GEN CC STK DIAB HTN hCV32160712 rs11079160 CE_STK GEN TThCV32160712 rs11079160 CE_STK REC TT hCV32160712 rs11079160 CE_STK ADD ThCV32160712 rs11079160 EO_STK AGE MALE REC TT DIAB HTN hCV32160712rs11079160 EO_STK AGE MALE GEN TT DIAB HTN hCV32160712 rs11079160ISCHEMIC_ GEN TT STK hCV32160712 rs11079160 ISCHEMIC_ REC TT STKhCV1619596 rs1048621  SDCBP2 CE_STK AGE MALE GEN AG DIAB HTN hCV1619596rs1048621  SDCBP2 CE_STK AGE MALE DOM AG or AA DIAB HTN hCV1619596rs1048621  SDCBP2 CE_STK ADD A hCV1619596 rs1048621  SDCBP2 EO_STK DOMAG or AA hCV1619596 rs1048621  SDCBP2 EO_STK GEN AG hCV1619596rs1048621  SDCBP2 EO_STK ADD A hCV1619596 rs1048621  SDCBP2 EO_STK AGEMALE DOM AG or AA DIAB HTN hCV1619596 rs1048621  SDCBP2 EO_STK AGE MALEGEN AG DIAB HTN hCV1619596 rs1048621  SDCBP2 ISCHEMIC_ AGE MALE GEN AGSTK DIAB HTN hCV1619596 rs1048621  SDCBP2 ISCHEMIC_ AGE MALE DOM AG orAA STK DIAB HTN hCV1619596 rs1048621  SDCBP2 ISCHEMIC_ ADD A STKhCV2358247 rs415989  WFDC3 RECURRENT_ DOM GA or GG STK hCV2358247rs415989  WFDC3 RECURRENT_ GEN GA STK hCV2358247 rs415989  WFDC3RECURRENT_ ADD G STK hCV29537898 rs6073804  NOHD_STK GEN TC hCV29537898rs6073804  NOHD_STK DOM TC or TT hCV29537898 rs6073804  RECURRENT_ DOMTC or TT STK hCV29537898 rs6073804  RECURRENT_ ADD T STK hCV29537898rs6073804  RECURRENT_ GEN TC STK hCV1723718 rs12481805 UMODL1 EO_STK AGEMALE REC AA DIAB HTN hCV1723718 rs12481805 UMODL1 LACUNAR_ REC AA STKhCV1723718 rs12481805 UMODL1 LACUNAR_ GEN AA STK ProbChi 95% 95% Sq (2-Odds Lower Upper sided p- PVALUE_ hCV # Ratio CL CL value) 2DFhCV1958451 1.753 0.99 3.106 0.0543 0.15583 hCV1958451 1.676 0.974 2.8840.0623 . hCV1958451 1.565 0.952 2.573 0.0775 0.15311 hCV1958451 1.6280.935 2.835 0.0852 0.15583 hCV1958451 1.932 0.987 3.781 0.0546 0.06739hCV27494483 1.575 1.084 2.287 0.0171 0.05794 hCV27494483 1.564 1.0812.263 0.0176 . hCV27494483 1.522 1.065 2.175 0.0211 . hCV27494483 1.3070.967 1.765 0.0814 . hCV27494483 1.291 0.966 1.725 0.0847 . hCV274944831.306 0.963 1.771 0.0859 0.21896 hCV27504565 2.619 1.242 5.524 0.01150.04076 hCV27504565 2.434 1.184 5.002 0.0155 . hCV27504565 2.336 1.1274.841 0.0225 0.04076 hCV27504565 1.922 1.077 3.43 0.027 0.08635hCV27504565 1.858 1.06 3.256 0.0306 . hCV27504565 1.821 1.032 3.2120.0385 0.08635 hCV27504565 1.416 0.957 2.095 0.0819 0.13029 hCV275045651.527 0.985 2.369 0.0585 0.11469 hCV27504565 1.706 0.952 3.055 0.07250.18169 hCV27504565 1.811 0.973 3.371 0.061 0.10231 hCV27504565 1.4870.943 2.346 0.0877 0.12763 hCV27504565 2.79 0.968 8.046 0.0575 0.15677hCV27504565 2.47 0.893 6.833 0.0817 . hCV8754449 2.155 1.043 4.4520.0381 0.11587 hCV8754449 2.021 1.004 4.065 0.0486 . hCV8754449 1.7681.002 3.119 0.049 0.1425  hCV8754449 1.724 0.995 2.986 0.0521 .hCV8754449 1.698 0.974 2.96 0.0619 0.1425  hCV8754449 1.949 0.96 3.9550.0647 0.11587 hCV8754449 2.615 0.909 7.524 0.0747 0.20413 hCV87544492.421 0.876 6.693 0.0883 . hCV2091644 1.275 0.956 1.699 0.0984 .hCV8820007 1.597 0.953 2.678 0.0757 0.18574 hCV8820007 1.387 0.953 2.020.0876 0.11797 hCV8820007 1.511 0.927 2.463 0.0975 0.21063 hCV88200071.624 1.065 2.478 0.0243 0.01745 hCV8820007 1.751 1.027 2.984 0.03960.07825 hCV8820007 1.543 0.929 2.564 0.094 . hCV8820007 1.404 0.9372.102 0.0998 . hCV11354788 1.379 1.016 1.871 0.0394 . hCV11354788 1.4191.012 1.99 0.0423 . hCV11354788 1.397 0.987 1.977 0.0592 0.11826hCV11354788 1.274 0.99 1.639 0.0597 . hCV11354788 1.275 0.984 1.6530.066 0.16972 hCV11354788 1.231 0.982 1.542 0.0711 . hCV11354788 1.5011.205 1.869 0.0003 . hCV11354788 1.56 1.216 2.002 0.0005 . hCV113547881.633 1.215 2.196 0.0011 . hCV11354788 1.712 1.227 2.39 0.0016 .hCV11354788 1.51 1.166 1.956 0.0018 0.00137 hCV11354788 1.652 1.17 2.3320.0043 0.00498 hCV11354788 2.198 1.061 4.556 0.0341 0.00137 hCV113547881.996 0.966 4.125 0.0619 . hCV11354788 2.533 0.921 6.962 0.0716 0.00498hCV11354788 1.432 1.068 1.922 0.0165 . hCV11354788 1.413 1.06 1.8830.0184 . hCV11354788 1.365 1.053 1.768 0.0186 . hCV11354788 1.466 1.0572.032 0.0217 . hCV11354788 1.396 1.038 1.876 0.0273 0.05898 hCV113547881.423 1.017 1.991 0.0396 0.0564  hCV11354788 1.356 1.113 1.652 0.0025 .hCV11354788 1.309 1.097 1.563 0.0029 . hCV11354788 1.346 1.099 1.650.0041 0.0099  hCV11354788 1.367 1.077 1.735 0.0102 . hCV11354788 1.4041.077 1.831 0.0122 . hCV11354788 1.376 1.047 1.809 0.022 0.03661hCV11354788 1.31 1.083 1.585 0.0053 . hCV11354788 1.345 1.086 1.6660.0065 . hCV11354788 1.321 1.059 1.647 0.0135 0.02034 hCV11354788 1.3541.052 1.743 0.0188 . hCV11354788 1.375 1.036 1.825 0.0275 . hCV113547881.332 0.995 1.784 0.0544 0.06231 hCV11354788 1.248 0.99 1.573 0.06130.17362 hCV11354788 1.233 0.984 1.545 0.0692 . hCV11354788 1.295 0.9531.758 0.0982 . hCV11354788 2.096 1.252 3.509 0.0049 0.01709 hCV113547881.962 1.187 3.243 0.0086 . hCV11354788 1.701 1.072 2.7 0.0241 .hCV11354788 1.383 0.979 1.955 0.066 . hCV11354788 1.382 0.968 1.9730.075 0.1844  hCV11354788 1.321 0.972 1.796 0.0752 . hCV16158671 1.4151.045 1.915 0.0248 . hCV16158671 1.442 1.028 2.023 0.0339 . hCV161586711.304 1.013 1.679 0.039 . hCV16158671 1.257 1.005 1.573 0.0456 .hCV16158671 1.302 1.003 1.69 0.047 0.11865 hCV16158671 1.397 0.986 1.980.06 0.07966 hCV16158671 1.509 1.213 1.879 0.0002 . hCV16158671 1.5851.235 2.035 0.0003 . hCV16158671 1.543 1.191 1.999 0.001 0.00106hCV16158671 1.631 1.216 2.189 0.0011 . hCV16158671 1.733 1.241 2.420.0012 . hCV16158671 1.684 1.192 2.381 0.0032 0.00458 hCV16158671 2.0831.015 4.275 0.0454 0.00106 hCV16158671 1.883 0.92 3.853 0.0832 .hCV16158671 2.319 0.869 6.191 0.093 0.00458 hCV16158671 1.426 1.0691.901 0.0156 . hCV16158671 1.364 1.055 1.763 0.0178 . hCV16158671 1.4091.052 1.887 0.0215 . hCV16158671 1.415 1.051 1.905 0.022 0.05284hCV16158671 1.448 1.044 2.008 0.0267 . hCV16158671 1.409 1.006 1.9750.0461 0.07117 hCV16158671 1.376 1.13 1.677 0.0015 . hCV16158671 1.3241.11 1.579 0.0018 . hCV16158671 1.365 1.113 1.674 0.0028 0.00631hCV16158671 1.375 1.085 1.742 0.0083 . hCV16158671 1.413 1.083 1.8430.0109 . hCV16158671 1.378 1.047 1.813 0.0222 0.03074 hCV16158671 1.3271.099 1.603 0.0032 . hCV16158671 1.366 1.103 1.691 0.0042 . hCV161586711.337 1.072 1.668 0.0101 0.01299 hCV16158671 1.366 1.063 1.754 0.0147 .hCV16158671 1.384 1.042 1.838 0.0247 . hCV16158671 1.33 0.992 1.7830.0569 0.04871 hCV16158671 2.103 0.891 4.961 0.0896 0.04871 hCV161586711.251 0.998 1.568 0.0518 . hCV16158671 1.259 0.998 1.588 0.0525 0.14733hCV16158671 1.206 0.985 1.475 0.0696 . hCV16158671 1.274 0.967 1.6790.0852 . hCV16158671 1.297 0.954 1.761 0.0967 . hCV16158671 2.087 1.243.512 0.0056 0.01904 hCV16158671 1.943 1.171 3.225 0.0102 . hCV161586711.671 1.053 2.652 0.0294 . hCV16158671 1.375 0.971 1.948 0.0728 .hCV16158671 1.38 0.964 1.975 0.0786 0.19939 hCV16158671 1.307 0.9611.776 0.0879 . hCV16336 1.377 1.032 1.837 0.0298 . hCV16336 1.315 1.0131.707 0.0399 . hCV16336 1.39 0.96 2.013 0.0812 . hCV16336 1.523 1.1472.022 0.0036 . hCV16336 1.525 1.126 2.066 0.0065 . hCV16336 1.49 1.0332.148 0.0328 . hCV16336 1.52 1.028 2.247 0.036 . hCV16336 3.625 0.82515.926 0.0881 0.01511 hCV16336 1.659 1.156 2.381 0.0061 . hCV16336 1.5591.11 2.188 0.0103 . hCV16336 1.389 1.014 1.904 0.0407 . hCV16336 1.3551.01 1.819 0.0427 . hCV16336 1.379 1.127 1.686 0.0018 . hCV16336 1.411.131 1.758 0.0023 . hCV16336 1.377 1.052 1.803 0.0198 . hCV16336 1.4171.056 1.901 0.0203 . hCV16336 1.227 0.99 1.521 0.0619 . hCV16336 1.2480.986 1.581 0.0658 . hCV16336 1.345 1.046 1.73 0.0211 . hCV16336 1.31.035 1.633 0.0244 . hCV16336 1.39 0.999 1.935 0.0508 . hCV16336 1.3460.997 1.816 0.0521 . hCV26478797 1.205 0.965 1.505 0.099 . hCV114258011.99 1.402 2.824 0.0001 0.0005  hCV11425801 1.726 1.251 2.38 0.0009 .hCV11425801 1.539 1.183 2.002 0.0013 0.00531 hCV11425801 1.481 1.1591.892 0.0017 . hCV11425801 1.179 1.019 1.363 0.0271 . hCV11425801 1.3851.028 1.865 0.0323 0.00531 hCV11425801 1.18 0.974 1.429 0.0913 .hCV11425801 1.639 1.226 2.192 0.0009 0.00345 hCV11425801 1.718 1.229 2.40.0015 0.00399 hCV11425801 1.484 1.135 1.939 0.0038 . hCV11425801 1.4831.092 2.015 0.0116 . hCV11425801 1.617 1.235 2.116 0.0005 0.00176hCV11425801 1.453 1.135 1.86 0.003 . hCV11425801 1.321 1.082 1.6120.0062 0.02335 hCV11425801 1.276 1.062 1.534 0.0094 . hCV11425801 1.1040.985 1.236 0.0889 . hCV11425801 1.826 1.186 2.811 0.0063 0.01078hCV11425801 1.51 1.014 2.25 0.0427 . hCV11425801 1.368 0.973 1.9230.0715 0.11508 hCV11425801 1.641 1.229 2.19 0.0008 0.00304 hCV114258011.472 1.13 1.916 0.0041 . hCV11425801 1.276 1.043 1.559 0.0176 .hCV11425801 1.295 1.041 1.61 0.0201 0.05622 hCV11425801 1.12 0.991 1.2660.07 . hCV11425801 1.244 0.973 1.591 0.0821 0.05622 hCV11425801 1.6891.268 2.251 0.0003 . hCV11425801 1.48 1.176 1.862 0.0008 0.00363hCV11425801 1.393 1.125 1.725 0.0023 . hCV11425801 1.126 0.989 1.2820.0732 . hCV11425801 1.249 0.96 1.625 0.0971 0.00363 hCV11425801 1.6360.988 2.71 0.0556 0.12066 hCV11425801 1.368 0.951 1.967 0.091 0.22257hCV11425842 1.483 1.042 2.111 0.0286 . hCV11425842 1.508 1.036 2.1950.032 0.08825 hCV11425842 1.281 0.979 1.676 0.0707 . hCV11425842 1.4450.961 2.172 0.077 0.08825 hCV11425842 1.292 0.972 1.717 0.0777 0.19224hCV11425842 1.44 1.056 1.965 0.0214 0.06697 hCV11425842 1.4 1.047 1.8710.0232 . hCV11425842 1.497 1.048 2.138 0.0267 0.08575 hCV11425842 1.4181.016 1.978 0.0399 . hCV11425842 1.338 0.953 1.878 0.0927 0.06697hCV11425842 1.334 0.998 1.785 0.0518 0.1427  hCV11425842 1.309 0.9971.719 0.0525 . hCV11425842 1.435 1.028 2.005 0.0341 0.10566 hCV114258421.379 1.008 1.886 0.0444 . hCV1209800 1.54 0.995 2.384 0.0529 .hCV1209800 1.497 0.985 2.277 0.059 . hCV16134786 1.287 1.044 1.587 0.018. hCV16134786 1.967 1.08 3.581 0.0269 0.0477  hCV16134786 1.845 1.023.336 0.0428 . hCV16134786 1.283 0.999 1.65 0.0513 . hCV16134786 2.1491.196 3.86 0.0105 0.0372  hCV16134786 2.114 1.189 3.76 0.0108 .hCV16134786 1.243 0.98 1.578 0.073 . hCV16134786 1.158 0.984 1.3630.0777 . hCV16134786 1.501 0.953 2.365 0.0799 0.16516 hCV25651109 8.2551.015 67.158 0.0484 0.13989 hCV25651109 8.232 1.012 66.954 0.0487 .hCV25651109 7.978 0.963 66.101 0.0542 0.13989 hCV25651109 6.169 0.74351.25 0.0921 0.2415  hCV25651109 5.892 0.724 47.938 0.0973 . hCV256511095.866 0.721 47.736 0.0981 0.2415  hCV30308202 1.354 1.016 1.803 0.0384 .hCV30308202 3.706 1.016 13.521 0.0473 0.12903 hCV30308202 3.537 0.97812.795 0.0542 . hCV30308202 1.349 0.975 1.868 0.0712 . hCV30308202 3.2040.854 12.028 0.0845 0.12903 hCV30308202 2.419 0.856 6.839 0.0956 0.11116hCV3082219 1.273 0.982 1.65 0.0681 . hCV3082219 1.399 1.049 1.867 0.0225. hCV3082219 1.424 1.035 1.959 0.03 . hCV3082219 1.391 1.003 1.93 0.04830.07365 hCV3082219 1.213 0.991 1.485 0.0608 . hCV3082219 1.227 0.9841.529 0.0688 . hCV3082219 1.214 0.969 1.52 0.0917 0.17242 hCV89420321.484 1.127 1.954 0.0049 . hCV8942032 1.488 1.12 1.978 0.0062 0.01912hCV8942032 1.394 1.092 1.78 0.0077 . hCV8942032 1.513 1.09 2.101 0.01340.04543 hCV8942032 1.486 1.083 2.038 0.0142 . hCV8942032 1.37 1.037 1.810.0265 . hCV8942032 1.383 1.056 1.811 0.0183 0.061  hCV8942032 1.3411.035 1.737 0.0262 . hCV8942032 1.241 0.991 1.554 0.0604 . hCV89420321.208 0.988 1.476 0.0658 0.17422 hCV8942032 1.178 0.972 1.428 0.0949 .hCV8942032 1.803 1.207 2.694 0.004 . hCV8942032 1.64 1.165 2.307 0.0046. hCV8942032 1.77 1.166 2.689 0.0074 0.01502 hCV8942032 1.418 1.0361.942 0.0294 . hCV8942032 1.328 1.023 1.725 0.0333 . hCV8942032 1.4051.01 1.954 0.0435 0.09148 hCV8942032 1.358 1.021 1.807 0.0355 0.09951hCV8942032 1.309 0.994 1.723 0.0554 . hCV8942032 1.218 0.98 1.513 0.07490.10394 hCV8942032 1.419 1.047 1.923 0.0242 0.07825 hCV8942032 1.3771.027 1.845 0.0323 . hCV8942032 1.244 0.992 1.559 0.0585 0.1603 hCV8942032 1.269 0.983 1.637 0.0672 . hCV8942032 1.211 0.975 1.5040.0833 . hCV8942032 1.953 1.219 3.129 0.0054 . hCV8942032 1.965 1.2063.201 0.0067 0.02072 hCV8942032 1.728 1.15 2.594 0.0084 . hCV89420321.415 1.001 2.001 0.0494 0.14433 hCV8942032 1.384 0.992 1.931 0.0561 .hCV8942032 1.269 0.959 1.68 0.0956 . hCV25596936 1.432 1.071 1.9130.0153 0.03518 hCV25596936 1.345 1.017 1.779 0.038 . hCV25596936 1.2630.997 1.601 0.0533 0.04107 hCV25596936 1.433 0.981 2.092 0.0627 0.15123hCV25596936 1.302 1.01 1.679 0.0419 0.06504 hCV25596936 1.438 1.1081.865 0.0063 0.01473 hCV25596936 1.352 1.052 1.736 0.0183 . hCV255969361.224 0.981 1.526 0.0731 . hCV27511436 2.706 1.389 5.271 0.0034 0.00764hCV27511436 2.877 1.272 6.508 0.0111 0.03448 hCV27511436 2.231 1.18 4.220.0136 . hCV27511436 2.105 1.11 3.993 0.0227 0.00764 hCV27511436 2.3971.108 5.184 0.0263 . hCV27511436 2.271 1.046 4.93 0.0381 0.03448hCV27511436 2.392 1.294 4.422 0.0054 0.00015 hCV27511436 3.084 1.3836.875 0.0059 0.00609 hCV27511436 2.257 1.055 4.828 0.0359 . hCV275114362.025 0.943 4.352 0.0705 0.00609 hCV27511436 1.647 0.917 2.958 0.0946 .hCV27511436 5.062 2.211 11.593 0.0001 0.00053 hCV27511436 4.226 1.9019.394 0.0004 . hCV27511436 4.83 1.964 11.882 0.0006 0.00223 hCV275114363.983 1.786 8.882 0.0007 0.00053 hCV27511436 3.916 1.653 9.279 0.0019 .hCV27511436 3.668 1.542 8.725 0.0033 0.00223 hCV27511436 3.449 1.7986.618 0.0002 0.00063 hCV27511436 2.217 1.397 3.521 0.0007 . hCV275114362.78 1.498 5.158 0.0012 . hCV27511436 2.59 1.392 4.82 0.0027 0.00063hCV27511436 2.033 1.277 3.236 0.0028 0.00001 hCV27511436 12.63 2.35667.742 0.0031 0.00773 hCV27511436 8.049 1.905 34.008 0.0046 0.00667hCV27511436 9.88 1.896 51.473 0.0065 . hCV27511436 9.1 1.743 47.4990.0088 0.00773 hCV27511436 6.318 1.528 26.128 0.0109 . hCV27511436 5.8581.413 24.288 0.0148 0.00667 hCV27511436 2.83 1.661 4.824 0.0001 0.00002hCV27511436 3.231 1.612 6.479 0.001 0.00243 hCV27511436 2.088 1.2583.467 0.0044 . hCV27511436 2.586 1.334 5.012 0.0049 . hCV27511436 2.41.235 4.665 0.0098 0.00243 hCV27511436 1.891 1.135 3.149 0.0144 0.00002hCV27511436 3.955 1.807 8.657 0.0006 0.00244 hCV27511436 2.827 1.5555.142 0.0007 . hCV27511436 2.657 1.457 4.843 0.0014 0.00023 hCV275114363.312 1.571 6.985 0.0017 . hCV27511436 3.137 1.483 6.636 0.0028 0.00244hCV29401764 1.633 0.952 2.798 0.0746 0.17293 hCV15857769 1.187 1.0111.394 0.0361 . hCV15857769 1.255 1.011 1.557 0.0391 . hCV15857769 1.230.979 1.545 0.0756 0.1026  hCV15857769 1.532 0.946 2.48 0.0827 0.21882hCV15857769 1.36 0.947 1.952 0.096 0.1026  hCV15857769 1.295 1.029 1.630.0275 0.0333  hCV15857769 1.209 0.97 1.507 0.0919 . hCV15857769 1.2521.05 1.493 0.0124 0.04329 hCV15857769 1.219 1.031 1.441 0.0203 .hCV15857769 1.117 0.983 1.27 0.0904 . hCV15857769 1.263 1.043 1.530.0167 0.05587 hCV15857769 1.228 1.024 1.474 0.0271 . hCV15857769 1.2261.013 1.483 0.0365 . hCV15857769 1.224 1.001 1.497 0.0489 0.11225hCV15857769 1.149 0.996 1.327 0.057 . hCV15857769 1.788 1.299 2.4630.0004 0.00102 hCV15857769 1.641 1.203 2.238 0.0018 . hCV15857769 1.7331.112 2.701 0.0151 0.04261 hCV15857769 1.596 1.042 2.443 0.0315 .hCV15857769 1.259 1.003 1.58 0.0471 . hCV29539757 1.401 0.977 2.0090.0671 0.0978  hCV1348610 1.307 1.014 1.685 0.0389 0.11763 hCV13486101.262 0.993 1.602 0.0567 . hCV1348610 1.285 0.981 1.683 0.0688 0.15881hCV1348610 1.283 0.96 1.714 0.0923 0.22581 hCV26505812 1.363 0.956 1.9430.0866 . hCV26505812 1.32 0.959 1.818 0.0886 . hCV2169762 1.479 1.1721.866 0.001 0.00436 hCV2169762 1.422 1.139 1.774 0.0018 . hCV21697621.216 1.033 1.433 0.0189 . hCV2169762 1.401 1.046 1.876 0.0237 .hCV2169762 1.41 1.038 1.916 0.0281 0.07665 hCV2169762 1.25 1.003 1.5590.0473 . hCV2169762 1.493 0.946 2.357 0.0852 . hCV2169762 1.246 1.0521.476 0.0108 . hCV2169762 1.233 1.043 1.456 0.014 . hCV2169762 1.311.046 1.641 0.0187 . hCV2169762 1.236 1.035 1.476 0.0192 0.04864hCV2169762 1.536 1.045 2.259 0.0291 0.03859 hCV2169762 1.148 1.014 1.3010.0296 . hCV2169762 1.258 0.991 1.597 0.0589 0.03859 hCV2169762 1.3820.955 2 0.0861 . hCV2169762 1.362 0.949 1.955 0.0934 . hCV2169762 1.351.125 1.619 0.0012 . hCV2169762 1.354 1.116 1.642 0.0021 0.00545hCV2169762 1.218 1.064 1.395 0.0042 . hCV2169762 1.281 1.069 1.5340.0073 . hCV2169762 1.386 1.089 1.763 0.0079 . hCV2169762 1.347 1.0441.737 0.0221 0.02354 hCV2169762 1.553 1.031 2.34 0.035 0.02354hCV2169762 1.335 0.985 1.809 0.063 0.00545 hCV2169762 1.497 0.971 2.3080.0677 0.17878 hCV2169762 1.188 0.981 1.438 0.0774 . hCV2169762 1.4220.939 2.153 0.0966 . hCV27830265 2.437 1.292 4.596 0.0059 0.01855hCV27830265 2.354 1.254 4.421 0.0077 . hCV27830265 1.051 0.0204 1.381.812 . hCV27830265 1.256 1.027 1.535 0.0262 . hCV27830265 2.705 1.096.711 0.0318 0.04449 hCV27830265 2.508 1.018 6.179 0.0456 . hCV278302651.356 0.997 1.845 0.0522 . hCV27830265 1.294 0.988 1.697 0.0616 .hCV27830265 1.322 0.979 1.786 0.0687 . hCV27830265 1.302 0.956 1.7720.0938 0.17365 hCV27830265 1.909 1.098 3.32 0.0219 0.06853 hCV278302651.88 1.084 3.26 0.0246 . hCV27830265 1.231 0.99 1.53 0.0618 .hCV27830265 2.011 0.94 4.304 0.0719 0.12112 hCV27830265 1.923 0.9024.099 0.0903 . hCV27830265 1.146 0.977 1.344 0.0941 . hCV27830265 1.3910.982 1.972 0.0632 . hCV27830265 1.408 0.958 2.069 0.082 . hCV278302651.889 1.048 3.404 0.0342 0.10105 hCV27830265 1.859 1.035 3.339 0.0381 .hCV27830265 1.246 0.988 1.571 0.0637 . hCV27830265 1.376 1.074 1.7610.0114 . hCV27830265 2.132 1.172 3.878 0.0132 0.02459 hCV27830265 1.2481.042 1.493 0.0158 . hCV27830265 2.037 1.124 3.693 0.019 . hCV278302651.386 1.051 1.83 0.021 . hCV27830265 1.335 1.004 1.775 0.0472 0.03807hCV27830265 1.221 0.996 1.497 0.0553 . hCV27830265 2.187 0.939 5.0930.0697 0.03807 hCV27830265 3.032 1.42 6.474 0.0042 . hCV27830265 2.9071.354 6.243 0.0062 0.01156 hCV27830265 4.128 1.238 13.766 0.021 .hCV27830265 4.048 1.205 13.592 0.0237 0.06695 hCV1053082 2.424 1.1015.338 0.028 . hCV1053082 2.412 1.089 5.342 0.03 0.08891 hCV1053082 2.4521.079 5.571 0.0322 0.08891 hCV1053082 2.519 1.057 6.004 0.0372 0.11133hCV1053082 2.464 1.039 5.844 0.0406 . hCV1053082 1.228 1.001 1.5080.0494 . hCV1053082 2.339 0.958 5.715 0.0622 0.11133 hCV1053082 1.2330.972 1.564 0.084 . hCV1053082 2.443 1.139 5.24 0.0218 . hCV10530822.453 1.139 5.282 0.0219 0.07158 hCV1053082 2.419 1.101 5.313 0.02780.07158 hCV1053082 1.306 1.002 1.703 0.0483 . hCV1053082 2.182 0.8945.324 0.0865 0.11774 hCV1053082 1.297 0.959 1.752 0.0909 . hCV10530822.441 1.274 4.675 0.0071 . hCV1053082 2.438 1.267 4.689 0.0076 0.02673hCV1053082 2.449 1.249 4.801 0.0091 0.02673 hCV1053082 1.695 1.052 2.7320.0302 0.08337 hCV1053082 1.658 1.032 2.664 0.0365 . hCV1053082 1.5770.965 2.576 0.0691 0.08337 hCV1053082 1.152 0.989 1.343 0.0698 .hCV1053082 2.225 1.109 4.465 0.0244 . hCV1053082 2.282 1.109 4.692 0.0250.07672 hCV1053082 2.202 1.092 4.438 0.0274 0.07672 hCV1053082 1.7151.006 2.924 0.0475 0.13875 hCV1053082 1.695 0.998 2.88 0.0509 .hCV1053082 1.651 0.955 2.855 0.0727 0.13875 hCV1053082 2.388 1.164 4.8970.0175 . hCV1053082 2.451 1.164 5.163 0.0183 0.05761 hCV1053082 2.361.145 4.866 0.02 0.05761 hCV1053082 1.684 0.963 2.945 0.0673 .hCV1053082 1.69 0.963 2.966 0.0674 0.18668 hCV1053082 1.672 0.939 2.9770.0808 0.18668 hCV1452085 2.844 0.95 8.517 0.0617 0.07446 hCV14520858.604 0.863 85.766 0.0666 0.00063 hCV1452085 4.953 1.405 17.456 0.01280.01831 hCV1452085 3.875 1.132 13.267 0.031 . hCV1452085 3.687 1.07512.65 0.038 0.01831 hCV1452085 2.892 0.881 9.491 0.0798 0.03384hCV1452085 12.05 0.995 145.92 0.0505 0.02942 hCV302629 1.268 0.982 1.6380.0684 0.16605 hCV11474611 1.408 0.962 2.061 0.0785 0.15447 hCV114746117.206 0.691 75.167 0.0988 0.25264 hCV11474611 7.176 0.688 74.834 0.0995. hCV1262973 1.33 0.99 1.789 0.0586 0.03312 hCV27892569 1.569 1.0222.409 0.0394 0.11153 hCV27892569 1.514 0.996 2.303 0.0525 . hCV278925691.184 0.993 1.412 0.06 . hCV27892569 1.139 0.982 1.32 0.0847 .hCV27077072 1.253 0.99 1.587 0.0605 . hCV27077072 1.308 0.967 1.770.0816 . hCV27077072 1.952 0.901 4.23 0.0899 0.22584 hCV32160712 1.931.061 3.512 0.0313 0.0843  hCV32160712 1.872 1.034 3.391 0.0385 .hCV32160712 1.213 0.988 1.489 0.0648 . hCV32160712 2.382 1.026 5.5320.0435 . hCV32160712 2.361 1.011 5.513 0.047 0.12823 hCV32160712 1.5630.953 2.565 0.0772 0.1756  hCV32160712 1.529 0.935 2.502 0.0907 .hCV1619596 1.412 1.038 1.92 0.0281 0.08963 hCV1619596 1.362 1.017 1.8230.0382 . hCV1619596 1.168 0.982 1.389 0.0794 . hCV1619596 1.314 1.031.677 0.0281 . hCV1619596 1.33 1.029 1.719 0.0292 0.08594 hCV16195961.205 0.993 1.461 0.0586 . hCV1619596 1.295 0.979 1.713 0.0699 .hCV1619596 1.298 0.967 1.741 0.0822 0.1932  hCV1619596 1.271 1.001 1.6120.0486 0.14298 hCV1619596 1.239 0.989 1.554 0.0629 . hCV1619596 1.1250.985 1.284 0.0826 . hCV2358247 1.521 0.989 2.34 0.0561 . hCV23582471.527 0.987 2.363 0.0574 0.16029 hCV2358247 1.468 0.978 2.204 0.0636 .hCV29537898 1.303 1.011 1.679 0.0406 0.06312 hCV29537898 1.258 0.981.614 0.0712 . hCV29537898 1.866 1.288 2.703 0.001 . hCV29537898 1.7491.25 2.448 0.0011 . hCV29537898 1.848 1.264 2.701 0.0015 0.00417hCV1723718 1.543 0.928 2.565 0.0944 . hCV1723718 1.773 1.119 2.8090.0147 . hCV1723718 1.632 1.011 2.633 0.045 0.02572

TABLE 21 ProbChi 95% 95% Sq (2- AD- GENO- Odds Lower Upper sided p-PVAL- hCV # rs # Gene OUTCOME JUST MODE TYPE Ratio CL CL value) UE_2DFhCV11548152 rs11580249 EO_STK AGE GEN TG 1.231 0.899 1.686 0.19470.43131 MALE DIAB HTN hCV1958451 rs2985822 MIER1 EO_STK DOM GT or 1.4090.879 2.258 0.1545 — GG hCV1958451 rs2985822 MIER1 ISCHEMIC_STK GEN GT1.279 0.909 1.8 0.1576 0.08689 hCV1958451 rs2985822 MIER1 LACUNAR_STKDOM GT or 1.638 0.857 3.131 0.1351 — GG hCV1958451 rs2985822 MIER1LACUNAR_STK AGE GEN GT 1.734 0.753 3.995 0.196 0.39776 MALE DIAB HTNhCV1958451 rs2985822 MIER1 NOHD_STK GEN GT 1.284 0.887 1.859 0.18490.03579 hCV1958451 rs2985822 MIER1 NONCE_STK GEN GT 1.361 0.915 2.0240.1281 0.13834 hCV27494483 rs3748743 SLC22A15 CE_STK AGE GEN TC 1.4330.867 2.366 0.1602 0.27105 MALE DIAB HTN hCV27504565 rs3219489 MUTYHISCHEMIC_STK DOM CG or 1.305 0.896 1.901 0.1656 — CC hCV27504565rs3219489 MUTYH NOHD_STK GEN CC 1.339 0.872 2.055 0.1821 0.11469hCV27504565 rs3219489 MUTYH NOHD_STK DOM CG or 1.407 0.922 2.146 0.1129— CC hCV27504565 rs3219489 MUTYH NOHD_STK AGE GEN CC 1.519 0.859 2.6830.1503 0.18169 MALE DIAB HTN hCV27504565 rs3219489 MUTYH NOHD_STK AGEDOM CG or 1.587 0.906 2.782 0.1066 — MALE CC DIAB HTN hCV27504565rs3219489 MUTYH NONCE_STK DOM CG or 1.351 0.871 2.095 0.1786 — CChCV27504565 rs3219489 MUTYH NONCE_STK AGE DOM CG or 1.593 0.877 2.8950.1265 — MALE CC DIAB HTN hCV27504565 rs3219489 MUTYH RECURRENT_STK AGEGEN CC 2.313 0.826 6.477 0.1106 0.15677 MALE DIAB HTN hCV31227848rs11809423 HIVEP3 ATHERO_STK GEN TC 1.404 0.927 2.128 0.1094 0.06604hCV31227848 rs11809423 HIVEP3 NOHD_STK GEN TC 1.284 0.889 1.853 0.18220.0563 hCV31227848 rs11809423 HIVEP3 NONCE_STK GEN TC 1.327 0.908 1.9390.1434 0.12332 hCV454333 rs10916581 NVL RECURRENT_STK GEN CT 5.03 0.66438.1 0.1179 0.09083 hCV454333 rs10916581 NVL RECURRENT_STK GEN CC 3.7780.504 28.32 0.1959 0.09083 hCV454333 rs10916581 NVL RECURRENT_STK DOM CTor 4.101 0.548 30.66 0.1692 — CC hCV8754449 rs781226 TESK2 NOHD_STK GENCT 1.375 0.894 2.114 0.1474 0.25013 hCV8754449 rs781226 TESK2 NOHD_STKAGE GEN CT 1.508 0.856 2.656 0.1552 0.34108 MALE DIAB HTN hCV8754449rs781226 TESK2 NONCE_STK AGE GEN CT 1.536 0.841 2.803 0.1625 0.25117MALE DIAB HTN hCV8754449 rs781226 TESK2 RECURRENT_STK AGE GEN CC 2.3210.83 6.495 0.1087 0.20413 MALE DIAB HTN hCV2091644 rs1010 VAMP8 CE_STKGEN CC 1.287 0.933 1.776 0.1236 0.25285 hCV2091644 rs1010 VAMP8 CE_STKADD C 1.114 0.952 1.305 0.1788 — hCV2091644 rs1010 VAMP8 EO_STK AGE GENCT 1.238 0.912 1.682 0.1714 0.34826 MALE DIAB HTN hCV2091644 rs1010VAMP8 ISCHEMIC_STK GEN CC 1.189 0.927 1.524 0.1731 0.28614 hCV2091644rs1010 VAMP8 ISCHEMIC_STK REC CC 1.198 0.957 1.499 0.115 — hCV2091644rs1010 VAMP8 RECURRENT_STK AGE GEN CT 1.385 0.865 2.216 0.1753 0.3581MALE DIAB HTN hCV7425232 rs3900940 MYH15 EO_STK AGE DOM CT or 1.2080.913 1.596 0.1853 — MALE CC DIAB HTN hCV8820007 rs938390 ATHERO_STK GENTT 1.428 0.865 2.359 0.1639 0.18574 hCV8820007 rs938390 ATHERO_STK DOMTA or 1.486 0.906 2.437 0.1171 — TT hCV8820007 rs938390 ATHERO_STK AGEGEN TA 1.603 0.846 3.038 0.1475 0.28036 MALE DIAB HTN hCV8820007rs938390 CE_STK GEN TA 1.389 0.846 2.282 0.194 0.14033 hCV8820007rs938390 EO_STK GEN TA 1.523 0.889 2.609 0.1254 0.30388 hCV8820007rs938390 EO_STK DOM TA or 1.432 0.862 2.379 0.1661 — TT hCV8820007rs938390 EO_STK AGE GEN TA 1.659 0.904 3.046 0.1025 0.25362 MALE DIABHTN hCV8820007 rs938390 EO_STK AGE GEN TT 1.463 0.818 2.616 0.19980.25362 MALE DIAB HTN hCV8820007 rs938390 EO_STK AGE DOM TA or 1.5250.861 2.704 0.1482 — MALE TT DIAB HTN hCV8820007 rs938390 ISCHEMIC_STKAGE DOM TA or 1.382 0.871 2.194 0.1698 — MALE TT DIAB HTN hCV8820007rs938390 NOHD_STK AGE GEN TT 1.434 0.856 2.403 0.1711 0.07825 MALE DIABHTN hCV8820007 rs938390 NONCE_STK GEN TA 1.386 0.897 2.142 0.14120.28065 hCV8820007 rs938390 NONCE_STK AGE GEN TA 1.555 0.891 2.7130.1203 0.27256 MALE DIAB HTN hCV8820007 rs938390 NONCE_STK AGE DOM TA or1.431 0.845 2.423 0.1829 — MALE TT DIAB HTN hCV8820007 rs938390RECURRENT_STK GEN TA 1.702 0.812 3.567 0.1592 0.19862 hCV11354788rs12644625 LOC729065 CE_STK AGE REC TT 2.249 0.823 6.145 0.1141 — MALEDIAB HTN hCV11354788 rs12644625 LOC729065 EO_STK AGE GEN TT 2.129 0.7276.236 0.1683 0.0564 MALE DIAB HTN hCV11354788 rs12644625 LOC729065ISCHEMIC_STK AGE GEN TT 1.8 0.759 4.269 0.1821 0.03661 MALE DIAB HTNhCV11354788 rs12644625 LOC729065 NOHD_STK GEN TT 1.651 0.849 3.2130.1397 0.02034 hCV11354788 rs12644625 LOC729065 NOHD_STK REC TT 1.5520.799 3.015 0.1942 — hCV11354788 rs12644625 LOC729065 NOHD_STK AGE GENTT 1.985 0.81 4.86 0.1337 0.06231 MALE DIAB HTN hCV11354788 rs12644625LOC729065 NOHD_STK AGE REC TT 1.86 0.761 4.543 0.1733 — MALE DIAB HTNhCV11354788 rs12644625 LOC729065 NONCE_STK ADD T 1.186 0.967 1.4540.1013 — hCV11354788 rs12644625 LOC729065 NONCE_STK AGE GEN TC 1.2880.941 1.763 0.1139 0.25236 MALE DIAB HTN hCV11354788 rs12644625LOC729065 NONCE_STK AGE ADD T 1.261 0.955 1.666 0.102 — MALE DIAB HTNhCV15854171 rs2231137 ABCG2 CE_STK ADD C 1.357 0.865 2.129 0.184 —hCV16158671 rs2200733 ATHERO_STK AGE GEN TT 2.133 0.724 6.287 0.16960.07966 MALE DIAB HTN hCV16158671 rs2200733 CE_STK AGE REC TT 2.0540.774 5.452 0.1483 — MALE DIAB HTN hCV16158671 rs2200733 EO_STK AGE GENTT 1.982 0.7 5.614 0.1976 0.07117 MALE DIAB HTN hCV16158671 rs2200733ISCHEMIC_STK GEN TT 1.506 0.815 2.783 0.1916 0.00631 hCV16158671rs2200733 ISCHEMIC_STK AGE GEN TT 1.874 0.819 4.292 0.1372 0.03074 MALEDIAB HTN hCV16158671 rs2200733 ISCHEMIC_STK AGE REC TT 1.743 0.763 3.9820.1873 — MALE DIAB HTN hCV16158671 rs2200733 NOHD_STK GEN TT 1.705 0.8983.238 0.1031 0.01299 hCV16158671 rs2200733 NOHD_STK REC TT 1.599 0.8443.032 0.1501 — hCV16158671 rs2200733 NOHD_STK AGE REC TT 1.973 0.8394.643 0.1195 — MALE DIAB HTN hCV16158671 rs2200733 NONCE_STK AGE GEN TC1.275 0.93 1.747 0.1316 0.22725 MALE DIAB HTN hCV16336 rs362277 HDATHERO_STK AGE ADD C 1.321 0.946 1.844 0.102 — MALE DIAB HTN hCV16336rs362277 HD CE_STK DOM CT or 3.411 0.777 14.97 0.104 — CC hCV16336rs362277 HD ISCHEMIC_STK GEN CC 1.847 0.825 4.133 0.1354 0.00758hCV16336 rs362277 HD ISCHEMIC_STK DOM CT or 1.751 0.783 3.914 0.1725 —CC hCV16336 rs362277 HD LACUNAR_STK AGE ADD C 1.368 0.892 2.097 0.1507 —MALE DIAB HTN hCV16336 rs362277 HD LACUNAR_STK AGE REC CC 1.389 0.8732.211 0.1656 — MALE DIAB HTN hCV31137507 rs7660668 CLOCK LACUNAR_STK GENCG 1.274 0.945 1.716 0.112 0.22027 hCV31137507 rs7660668 CLOCKLACUNAR_STK DOM CG or 1.21 0.909 1.612 0.1921 — CC hCV26478797 rs2015018CHSY-2 CE_STK ADD G 1.134 0.951 1.352 0.1602 — hCV26478797 rs2015018CHSY-2 CE_STK AGE REC GG 1.233 0.921 1.649 0.1593 — MALE DIAB HTNhCV26478797 rs2015018 CHSY-2 NOHD_STK REC GG 1.132 0.944 1.358 0.1816 —hCV26478797 rs2015018 CHSY-2 RECURRENT_STK GEN GA 1.613 0.804 3.2380.1787 0.30867 hCV26478797 rs2015018 CHSY-2 RECURRENT_STK GEN GG 1.7120.86 3.407 0.1255 0.30867 hCV26478797 rs2015018 CHSY-2 RECURRENT_STK DOMGA or 1.668 0.85 3.272 0.137 — GG hCV11425801 rs3805953 PEX6 ATHERO_STKAGE GEN CC 1.372 0.929 2.025 0.1116 0.0005 MALE DIAB HTN hCV11425801rs3805953 PEX6 CE_STK AGE GEN CT 1.287 0.913 1.812 0.1493 0.35182 MALEDIAB HTN hCV11425801 rs3805953 PEX6 EO_STK GEN CC 1.254 0.903 1.7390.1764 0.00345 hCV11425801 rs3805953 PEX6 EO_STK ADD C 1.133 0.961 1.3350.1372 hCV11425801 rs3805953 PEX6 ISCHEMIC_STK GEN CC 1.202 0.958 1.5080.1123 0.02335 hCV11425801 rs3805953 PEX6 ISCHEMIC_STK AGE ADD C 1.1160.959 1.3 0.1556 — MALE DIAB HTN hCV11425801 rs3805953 PEX6 LACUNAR_STKDOM CT or 1.235 0.897 1.7 0.1959 — CC hCV1142580 1 rs3805953 PEX6NOHD_STK AGE GEN CC 1.236 0.896 1.706 0.1968 0.00304 MALE DIAB HTNhCV11425801 rs3805953 PEX6 NOHD_STK AGE ADD C 1.124 0.958 1.32 0.1525 —MALE DIAB HTN hCV11425801 rs3805953 PEX6 NONCE_STK AGE GEN CC 1.2760.898 1.813 0.1732 0.00005 MALE DIAB HTN hCV11425801 rs3805953 PEX6NONCE_STK AGE ADD C 1.147 0.963 1.365 0.1237 — MALE DIAB HTN hCV11425801rs3805953 PEX6 RECURRENT_STK DOM CT or 1.28 0.912 1.798 0.1535 — CChCV11425801 rs3805953 PEX6 RECURRENT_STK AGE DOM CT or 1.403 0.885 2.2250.1498 — MALE CC DIAB HTN hCV11425842 rs10948059 GNMT ATHERO_STK GEN CC1.263 0.927 1.722 0.1392 0.19224 hCV11425842 rs10948059 GNMT ATHERO_STKADD C 1.109 0.953 1.29 0.1815 — hCV11425842 rs10948059 GNMT ATHERO_STKAGE ADD C 1.178 0.964 1.439 0.1101 — MALE DIAB HTN hCV11425842rs10948059 GNMT CE_STK AGE DOM CT or 1.272 0.898 1.8 0.1751 — MALE CCDIAB HTN hCV11425842 rs10948059 GNMT EO_STK ADD C 1.141 0.964 1.3520.126 — hCV11425842 rs10948059 GNMT EO_STK AGE GEN CC 1.302 0.883 1.920.1827 0.08575 MALE DIAB HTN hCV11425842 rs10948059 GNMT ISCHEMIC_STKAGE GEN CC 1.27 0.925 1.743 0.1389 0.1427 MALE DIAB HTN hCV11425842rs10948059 GNMT ISCHEMIC_STK AGE ADD C 1.113 0.951 1.303 0.1836 — MALEDIAB HTN hCV11425842 rs10948059 GNMT NOHD_STK AGE GEN CT 1.279 0.9381.745 0.1197 0.26094 MALE DIAB HTN hCV11425842 rs10948059 GNMT NOHD_STKAGE GEN CC 1.266 0.905 1.772 0.1686 0.26094 MALE DIAB HTN hCV11425842rs10948059 GNMT NOHD_STK AGE DOM CT or 1.274 0.953 1.703 0.1015 — MALECC DIAB HTN hCV11425842 rs10948059 GNMT NONCE_STK GEN CT 1.195 0.9321.531 0.1595 0.35697 hCV11425842 rs10948059 GNMT NONCE_STK DOM CT or1.184 0.938 1.495 0.1556 — CC hCV11425842 rs10948059 GNMT NONCE_STK AGEGEN CC 1.294 0.9 1.861 0.1646 0.10566 MALE DIAB HTN hCV16134786rs2857595 EO_STK GEN AG 1.207 0.929 1.568 0.1593 0.0477 hCV16134786rs2857595 EO_STK AGE ADD A 1.185 0.934 1.504 0.1629 — MALE DIAB HTNhCV16134786 rs2857595 ISCHEMIC_STK GEN AA 1.406 0.933 2.119 0.1030.26366 hCV16134786 rs2857595 ISCHEMIC_STK REC AA 1.392 0.928 2.0880.1098 — hCV16134786 rs2857595 ISCHEMIC_STK AGE ADD A 1.154 0.949 1.4020.1516 — MALE DIAB HTN hCV16134786 rs2857595 LACUNAR_STK AGE GEN AA 1.770.809 3.873 0.153 0.27205 MALE DIAB HTN hCV16134786 rs2857595LACUNAR_STK AGE ADD A 1.272 0.943 1.717 0.1157 — MALE DIAB HTNhCV16134786 rs2857595 LACUNAR_STK AGE DOM AG or 1.287 0.889 1.863 0.182— MALE AA DIAB HTN hCV16134786 rs2857595 NONCE_STK DOM AG or 1.151 0.9471.399 0.1584 — AA hCV16134786 rs2857595 NONCE_STK REC AA 1.448 0.9242.268 0.1062 — hCV25651109 rs35690712 SLC39A7 EO_STK GEN GC 5.189 0.55648.4 0.1484 0.34485 hCV25651109 rs35690712 SLC39A7 EO_STK GEN GG 4.6680.52 41.92 0.1689 0.34485 hCV25651109 rs35690712 SLC39A7 EO_STK DOM GCor 4.709 0.525 42.28 0.1664 — GG hCV25651109 rs35690712 SLC39A7ISCHEMIC_STK AGE GEN GC 4.69 0.505 43.57 0.1742 0.39506 MALE DIAB HTNhCV25651109 rs35690712 SLC39A7 ISCHEMIC_STK AGE GEN GG 4.372 0.486 39.350.1882 0.39506 MALE DIAB HTN hCV25651109 rs35690712 SLC39A7 ISCHEMIC_STKAGE DOM GC or 4.398 0.489 39.56 0.1864 — MALE GG DIAB HTN hCV25651109rs35690712 SLC39A7 NONCE_STK GEN GC 4.525 0.542 37.77 0.1632 0.26183hCV25651109 rs35690712 SLC39A7 NONCE_STK GEN GG 5.073 0.623 41.3 0.1290.26183 hCV25651109 rs35690712 SLC39A7 NONCE_STK ADD G 1.239 0.895 1.7130.1962 — hCV25651109 rs35690712 SLC39A7 NONCE_STK DOM GC or 5.026 0.61840.91 0.1312 — GG hCV30308202 rs9482985 LAMA2 CE_STK ADD G 1.168 0.9581.423 0.1237 — hCV30308202 rs9482985 LAMA2 CE_STK REC GG 1.179 0.9361.484 0.1621 — hCV30308202 rs9482985 LAMA2 CE_STK AGE GEN GC 1.724 0.7793.815 0.1792 0.26508 MALE DIAB HTN hCV30308202 rs9482985 LAMA2 CE_STKAGE GEN GG 1.878 0.867 4.07 0.1103 0.26508 MALE DIAB HTN hCV30308202rs9482985 LAMA2 CE_STK AGE ADD G 1.19 0.92 1.54 0.1851 — MALE DIAB HTNhCV30308202 rs9482985 LAMA2 CE_STK AGE DOM GC or 1.825 0.848 3.929 0.124— MALE GG DIAB HTN hCV30308202 rs9482985 LAMA2 RECURRENT_STK DOM GC or2.236 0.795 6.289 0.1272 — GG hCV30308202 rs9482985 LAMA2 RECURRENT_STKAGE ADD G 1.379 0.94 2.022 0.1002 — MALE DIAB HTN hCV3082219 rs1884833RFXDC1 EO_STK GEN AG 1.217 0.909 1.628 0.1874 0.16147 hCV3082219rs1884833 RFXDC1 EO_STK GEN AA 2.194 0.766 6.286 0.1434 0.16147hCV3082219 rs1884833 RFXDC1 EO_STK DOM AG or 1.262 0.949 1.677 0.1091 —AA hCV3082219 rs1884833 RFXDC1 EO_STK REC AA 2.096 0.733 5.993 0.1672 —hCV3082219 rs1884833 RFXDC1 LACUNAR_STK GEN AA 2.024 0.703 5.824 0.19110.07365 hCV3082219 rs1884833 RFXDC1 LACUNAR_STK AGE GEN AA 2.876 0.73511.26 0.1292 0.25425 MALE DIAB HTN hCV3082219 rs1884833 RFXDC1LACUNAR_STK AGE ADD A 1.288 0.89 1.865 0.18 — MALE DIAB HTN hCV3082219rs1884833 RFXDC1 LACUNAR_STK AGE REC AA 2.755 0.706 10.75 0.1444 — MALEDIAB HTN hCV3082219 rs1884833 RFXDC1 NOHD_STK GEN AA 1.762 0.835 3.7170.137 0.20951 hCV3082219 rs1884833 RFXDC1 NOHD_STK ADD A 1.171 0.9651.421 0.11 — hCV3082219 rs1884833 RFXDC1 NOHD_STK DOM AG or 1.158 0.9351.432 0.1783 — AA hCV3082219 rs1884833 RFXDC1 NOHD_STK REC AA 1.7150.814 3.612 0.1557 — hCV3082219 rs1884833 RFXDC1 NOHD_STK AGE GEN AA1.98 0.711 5.513 0.1912 0.41847 MALE DIAB HTN hCV3082219 rs1884833RFXDC1 NOHD_STK AGE REC AA 1.961 0.706 5.45 0.1964 — MALE DIAB HTNhCV8942032 rs1264352 DDR1 ATHERO_STK AGE GEN CG 1.315 0.937 1.846 0.11280.23534 MALE DIAB HTN hCV8942032 rs1264352 DDR1 ATHERO_STK AGE DOM CG or1.257 0.906 1.744 0.1707 — MALE CC DIAB HTN hCV8942032 rs1264352 DDR1CE_STK AGE GEN CG 1.299 0.916 1.842 0.1424 0.29178 MALE DIAB HTNhCV8942032 rs1264352 DDR1 CE_STK AGE ADD C 1.251 0.938 1.669 0.1269 —MALE DIAB HTN hCV8942032 rs1264352 DDR1 CE_STK AGE DOM CG or 1.307 0.9351.826 0.1175 — MALE CC DIAB HTN hCV8942032 rs1264352 DDR1 ISCHEMIC_STKADD C 1.119 0.948 1.321 0.1832 — hCV8942032 rs1264352 DDR1 LACUNAR_STKAGE GEN CC 2.104 0.743 5.961 0.1614 0.01502 MALE DIAB HTN hCV8942032rs1264352 DDR1 NOHD_STK DOM CG or 1.16 0.942 1.43 0.163 — CC hCV8942032rs1264352 DDR1 NOHD_STK AGE ADD C 1.211 0.951 1.541 0.1206 — MALE DIABHTN hCV8942032 rs1264352 DDR1 NONCE_STK ADD C 1.142 0.948 1.375 0.1628 —hCV25596936 rs6967117 EPHA1 ATHERO_STK ADD T 1.215 0.95 1.552 0.1207 —hCV25596936 rs6967117 EPHA1 ISCHEMIC_STK DOM TC or 1.181 0.941 1.4820.1522 — TT hCV25596936 rs6967117 EPHA1 LACUNAR_STK DOM TC or 1.3520.937 1.951 0.1065 — TT hCV25596936 rs6967117 EPHA1 NOHD_STK DOM TC or1.226 0.961 1.566 0.1014 — TT hCV29401764 rs7793552 LOC646588 ATHERO_STKAGE DOM CT or 1.501 0.896 2.513 0.123 — MALE CC DIAB HTN hCV15857769rs2924914 ATHERO_STK AGE ADD T 1.193 0.963 1.479 0.1061 — MALE DIAB HTNhCV15857769 rs2924914 ATHERO_STK AGE REC TT 1.456 0.92 2.305 0.1089 —MALE DIAB HTN hCV15857769 rs2924914 NOHD_STK ADD T 1.12 0.975 1.2870.1103 — hCV15857769 rs2924914 RECURRENT_STK AGE ADD T 1.255 0.909 1.7310.167 — MALE DIAB HTN hCV29539757 rs10110659 KCNQ3 ATHERO_STK GEN CA1.362 0.902 2.058 0.1417 0.31708 hCV29539757 rs10110659 KCNQ3 ATHERO_STKDOM CA or 1.297 0.875 1.925 0.1957 — CC hCV29539757 rs10110659 KCNQ3LACUNAR_STK GEN CA 1.453 0.843 2.504 0.1789 0.08401 hCV29539757rs10110659 KCNQ3 NONCE_STK DOM CA or 1.283 0.909 1.81 0.1572 — CChCV1348610 rs3739636 C9orf46 ATHERO_STK AGE GEN AG 1.304 0.945 1.7990.1062 0.25491 MALE DIAB HTN hCV1348610 rs3739636 C9orf46 ATHERO_STK AGEDOM AG or 1.242 0.918 1.682 0.1605 — MALE AA DIAB HTN hCV1348610rs3739636 C9orf46 CE_STK AGE GEN AG 1.24 0.895 1.719 0.1962 0.39368 MALEDIAB HTN hCV1348610 rs3739636 C9orf46 CE_STK AGE DOM AG or 1.238 0.9111.682 0.1722 — MALE AA DIAB HTN hCV1348610 rs3739636 C9orf46 NOHD_STKAGE DOM AG or 1.217 0.944 1.569 0.1306 — MALE AA DIAB HTN hCV1348610rs3739636 C9orf46 NONCE_STK AGE DOM AG or 1.226 0.933 1.61 0.144 — MALEAA DIAB HTN hCV1754669 rs2383206 C9P21 ATHERO_STK AGE REC GG 1.277 0.9131.784 0.1528 — MALE DIAB HTN hCV1754669 rs2383206 C9P21 NONCE_STK AGEREC GG 1.227 0.906 1.662 0.187 — MALE DIAB HTN hCV26505812 rs10757274C9P21 ISCHEMIC_STK AGE REC GG 1.207 0.912 1.599 0.1887 — MALE DIAB HTNhCV26505812 rs10757274 C9P21 NOHD_STK AGE REC GG 1.238 0.918 1.6690.1611 — MALE DIAB HTN hCV26505812 rs10757274 C9P21 NONCE_STK AGE GEN GG1.297 0.893 1.884 0.1714 0.23096 MALE DIAB HTN hCV15752716 rs2296436HPS1 CE_STK ADD T 1.242 0.914 1.686 0.1656 — hCV15752716 rs2296436 HPS1CE_STK REC TT 1.284 0.928 1.778 0.1311 — hCV2169762 rs1804689 HPS1ATHERO_STK GEN TT 1.293 0.914 1.829 0.1461 0.33606 hCV2169762 rs1804689HPS1 ATHERO_STK REC TT 1.282 0.92 1.787 0.1422 — hCV2169762 rs1804689HPS1 ATHERO_STK AGE GEN TT 1.446 0.902 2.316 0.1255 0.27749 MALE DIABHTN hCV2169762 rs1804689 HPS1 ATHERO_STK AGE REC TT 1.447 0.92 2.2760.1093 — MALE DIAB HTN hCV2169762 rs1804689 HPS1 EO_STK AGE GEN TT 1.490.926 2.397 0.1003 0.2272 MALE DIAB HTN hCV2169762 rs1804689 HPS1ISCHEMIC_STK GEN TT 1.22 0.921 1.617 0.1658 0.04864 hCV2169762 rs1804689HPS1 LACUNAR_STK GEN TG 1.273 0.941 1.721 0.1172 0.29125 hCV2169762rs1804689 HPS1 LACUNAR_STK DOM TG or 1.235 0.927 1.644 0.1491 — TThCV2169762 rs1804689 HPS1 LACUNAR_STK AGE GEN TG 1.345 0.919 1.97 0.12750.23974 MALE DIAB HTN hCV2169762 rs1804689 HPS1 LACUNAR_STK AGE ADD T1.246 0.953 1.63 0.1085 — MALE DIAB HTN hCV2169762 rs1804689 HPS1NOHD_STK AGE REC TT 1.351 0.914 1.999 0.1317 — MALE DIAB HTN hCV2169762rs1804689 HPS1 NONCE_STK GEN TT 1.229 0.897 1.683 0.1999 0.37015hCV2169762 rs1804689 HPS1 NONCE_STK ADD T 1.106 0.961 1.272 0.1591 —hCV2169762 rs1804689 HPS1 NONCE_STK AGE DOM TG or 1.193 0.923 1.5410.1783 — MALE TT DIAB HTN hCV27830265 rs12762303 ALOX5 ATHERO_STK DOM GAor 1.204 0.956 1.515 0.1143 — GG hCV27830265 rs12762303 ALOX5 ATHERO_STKAGE GEN GA 1.275 0.928 1.752 0.1331 0.04449 MALE DIAB HTN hCV27830265rs12762303 ALOX5 CE_STK GEN GG 1.591 0.788 3.212 0.1954 0.27948hCV27830265 rs12762303 ALOX5 CE_STK REC GG 1.637 0.813 3.293 0.1673 —hCV27830265 rs12762303 ALOX5 CE_STK AGE REC GG 1.967 0.73 5.302 0.1811 —MALE DIAB HTN hCV27830265 rs12762303 ALOX5 EO_STK GEN GG 1.724 0.7583.92 0.1937 0.27237 hCV27830265 rs12762303 ALOX5 EO_STK ADD G 1.2010.951 1.517 0.1236 — hCV27830265 rs12762303 ALOX5 EO_STK DOM GA or 1.1940.919 1.551 0.1835 — GG hCV27830265 rs12762303 ALOX5 ISCHEMIC_STK AGEDOM GA or 1.211 0.948 1.547 0.1246 — MALE GG DIAB HTN hCV27830265rs12762303 ALOX5 LACUNAR_STK GEN GA 1.242 0.911 1.692 0.1704 0.30411hCV27830265 rs12762303 ALOX5 LACUNAR_STK ADD G 1.237 0.944 1.621 0.1228— hCV27830265 rs12762303 ALOX5 LACUNAR_STK DOM GA or 1.258 0.93 1.7010.1365 — GG hCV27830265 rs12762303 ALOX5 LACUNAR_STK AGE GEN GA 1.3710.924 2.032 0.1169 0.17426 MALE DIAB HTN hCV27830265 rs12762303 ALOX5NOHD_STK ADD G 1.146 0.963 1.364 0.1236 — hCV27830265 rs12762303 ALOX5NOHD_STK AGE GEN GA 1.204 0.92 1.575 0.1757 0.16102 MALE DIAB HTNhCV27830265 rs12762303 ALOX5 NOHD_STK AGE GEN GG 1.82 0.823 4.024 0.13890.16102 MALE DIAB HTN hCV27830265 rs12762303 ALOX5 NOHD_STK AGE DOM GAor 1.244 0.958 1.615 0.1015 — MALE GG DIAB HTN hCV27830265 rs12762303ALOX5 NOHD_STK AGE REC GG 1.722 0.783 3.787 0.1768 — MALE DIAB HTNhCV27830265 rs12762303 ALOX5 NONCE_STK GEN GA 1.16 0.94 1.432 0.1660.02459 hCV27830265 rs12762303 ALOX5 NONCE_STK AGE REC GG 1.999 0.8644.627 0.1056 — MALE DIAB HTN hCV1053082 rs544115 NEU3 ATHERO_STK GEN CC1.629 0.864 3.07 0.1313 0.29853 hCV1053082 rs544115 NEU3 ATHERO_STK ADDC 1.139 0.935 1.387 0.1971 — hCV1053082 rs544115 NEU3 ATHERO_STK DOM CTor 1.597 0.851 2.997 0.1454 — CC hCV1053082 rs544115 NEU3 CE_STK GEN CC1.702 0.885 3.27 0.1107 0.13598 hCV1053082 rs544115 NEU3 CE_STK DOM CTor 1.618 0.845 3.097 0.1466 — CC hCV1053082 rs544115 NEU3 CE_STK AGE ADDC 1.237 0.945 1.619 0.1224 — MALE DIAB HTN hCV1053082 rs544115 NEU3EO_STK ADD C 1.172 0.933 1.471 0.172 — hCV1053082 rs544115 NEU3 EO_STKAGE DOM CT or 2.054 0.846 4.982 0.1115 — MALE CC DIAB HTN hCV1053082rs544115 NEU3 ISCHEMIC_STK REC CC 1.125 0.942 1.344 0.1924 — hCV1053082rs544115 NEU3 ISCHEMIC_STK AGE ADD C 1.164 0.943 1.436 0.1567 — MALEDIAB HTN hCV1053082 rs544115 NEU3 LACUNAR_STK GEN CT 2.025 0.775 5.2920.1499 0.33773 hCV1053082 rs544115 NEU3 LACUNAR_STK DOM CT or 1.8950.742 4.839 0.1815 — CC hCV1053082 rs544115 NEU3 LACUNAR_STK AGE GEN CT2.148 0.723 6.38 0.1685 0.38668 MALE DIAB HTN hCV1053082 rs544115 NEU3LACUNAR_STK AGE DOM CT or 2.036 0.708 5.851 0.1868 — MALE CC DIAB HTNhCV1053082 rs544115 NEU3 NOHD_STK ADD C 1.128 0.954 1.333 0.1577 —hCV1452085 rs12223005 TRIM22 CE_STK GEN CA 3.193 0.705 14.47 0.13210.27397 hCV1452085 rs12223005 TRIM22 CE_STK GEN CC 2.843 0.638 12.660.1703 0.27397 hCV1452085 rs12223005 TRIM22 CE_STK DOM CA or 2.902 0.65212.91 0.1619 — CC hCV1452085 rs12223005 TRIM22 CE_STK AGE GEN CA 4.1330.74 23.07 0.1058 0.25417 MALE DIAB HTN hCV1452085 rs12223005 TRIM22CE_STK AGE GEN CC 3.631 0.67 19.68 0.1347 0.25417 MALE DIAB HTNhCV1452085 rs12223005 TRIM22 CE_STK AGE DOM CA or 3.711 0.686 20.070.1279 — MALE CC DIAB HTN hCV1452085 rs12223005 TRIM22 EO_STK GEN CA2.362 0.762 7.322 0.1364 0.26957 hCV1452085 rs12223005 TRIM22 EO_STK DOMCA or 2.075 0.691 6.232 0.1935 — CC hCV1452085 rs12223005 TRIM22ISCHEMIC_STK GEN CA 1.97 0.824 4.714 0.1275 0.08218 hCV1452085rs12223005 TRIM22 ISCHEMIC_STK AGE GEN CC 2.207 0.757 6.44 0.14720.07446 MALE DIAB HTN hCV1452085 rs12223005 TRIM22 ISCHEMIC_STK AGE DOMCA or 2.31 0.793 6.727 0.1247 — MALE CC DIAB HTN hCV1452085 rs12223005TRIM22 LACUNAR_STK GEN CA 4.431 0.568 34.58 0.1556 0.00441 hCV1452085rs12223005 TRIM22 LACUNAR_STK AGE DOM CA or 4.519 0.471 43.37 0.1911 —MALE CC DIAB HTN hCV1452085 rs12223005 TRIM22 NOHD_STK GEN CA 2.4180.843 6.932 0.1004 0.16487 hCV1452085 rs12223005 TRIM22 NOHD_STK GEN CC2.082 0.739 5.866 0.1655 0.16487 hCV1452085 rs12223005 TRIM22 NOHD_STKDOM CA or 2.138 0.759 6.02 0.1502 — CC hCV1452085 rs12223005 TRIM22RECURRENT_STK AGE GEN CC 6.513 0.564 75.15 0.1332 0.02942 MALE DIAB HTNhCV1452085 rs12223005 TRIM22 RECURRENT_STK AGE DOM CA or 7.075 0.61880.97 0.1157 — MALE CC DIAB HTN hCV302629 rs9284183 UBAC2 EO_STK DOM GAor 1.217 0.954 1.553 0.1137 — GG hCV302629 rs9284183 UBAC2 EO_STK AGEGEN GA 1.219 0.91 1.633 0.1853 0.37831 MALE DIAB HTN hCV302629 rs9284183UBAC2 EO_STK AGE ADD G 1.156 0.927 1.442 0.1987 — MALE DIAB HTNhCV302629 rs9284183 UBAC2 EO_STK AGE DOM GA or 1.219 0.923 1.611 0.1632— MALE GG DIAB HTN hCV11474611 rs3814843 CALM1 ATHERO_STK DOM GT or1.345 0.925 1.956 0.1207 — GG hCV11474611 rs3814843 CALM1 ISCHEMIC_STKGEN GT 1.282 0.939 1.748 0.1173 0.13174 hCV11474611 rs3814843 CALM1ISCHEMIC_STK DOM GT or 1.222 0.902 1.656 0.1959 — GG hCV11474611rs3814843 CALM1 NOHD_STK GEN GT 1.32 0.946 1.842 0.1021 0.1136hCV11474611 rs3814843 CALM1 NOHD_STK DOM GT or 1.251 0.902 1.735 0.1789— GG hCV11474611 rs3814843 CALM1 NONCE_STK GEN GT 1.328 0.939 1.8770.1082 0.1417 hCV11474611 rs3814843 CALM1 NONCE_STK DOM GT or 1.2610.898 1.772 0.1806 — GG hCV11474611 rs3814843 CALM1 RECURRENT_STK GEN GT1.526 0.916 2.544 0.1047 0.2681 hCV11474611 rs3814843 CALM1RECURRENT_STK DOM GT or 1.429 0.86 2.374 0.168 — GG hCV1262973 rs229653PLEKHG3 ISCHEMIC_STK GEN AG 1.186 0.939 1.499 0.1523 0.00405 hCV1262973rs229653 PLEKHG3 RECURRENT_STK GEN AG 1.33 0.893 1.982 0.1605 0.3735hCV27892569 rs4903741 NRXN3 CE_STK DOM CT or 1.171 0.936 1.466 0.1674 —CC hCV27892569 rs4903741 NRXN3 LACUNAR_STK GEN CT 1.273 0.943 1.7190.1153 0.28645 hCV27892569 rs4903741 NRXN3 LACUNAR_STK DOM CT or 1.2410.93 1.656 0.143 — CC hCV27892569 rs4903741 NRXN3 NOHD_STK GEN CC 1.3330.917 1.939 0.1323 0.22016 hCV27892569 rs4903741 NRXN3 NOHD_STK DOM CTor 1.153 0.958 1.388 0.1327 — CC hCV27892569 rs4903741 NRXN3 NOHD_STKREC CC 1.278 0.885 1.845 0.191 — hCV27077072 rs8060368 RECURRENT_STK GENCC 1.564 0.889 2.75 0.1205 0.17139 hCV27077072 rs8060368 RECURRENT_STKAGE ADD C 1.308 0.947 1.806 0.1032 — MALE DIAB HTN hCV27077072 rs8060368RECURRENT_STK AGE DOM CT or 1.798 0.854 3.786 0.1226 — MALE CC DIAB HTNhCV2769503 rs4787956 CE_STK GEN GA 1.171 0.924 1.484 0.1909 0.3088hCV2769503 rs4787956 CE_STK ADD G 1.131 0.961 1.331 0.1373 — hCV2769503rs4787956 CE_STK DOM GA or 1.187 0.948 1.485 0.1354 — GG hCV2769503rs4787956 RECURRENT_STK GEN GA 1.27 0.919 1.753 0.1471 0.27579hCV31573621 rs11079818 SKAP1 ATHERO_STK REC TT 1.165 0.939 1.445 0.1653— hCV31573621 rs11079818 SKAP1 LACUNAR_STK AGE GEN TC 1.614 0.78 3.3410.1973 0.13048 MALE DIAB HTN hCV32160712 rs11079160 CE_STK DOM TA or1.181 0.928 1.501 0.1761 — TT hCV32160712 rs11079160 CE_STK AGE GEN TT1.93 0.872 4.27 0.1047 0.26509 MALE DIAB HTN hCV32160712 rs11079160CE_STK AGE REC TT 1.896 0.862 4.17 0.1116 — MALE DIAB HTN hCV32160712rs11079160 EO_STK GEN TT 1.734 0.829 3.629 0.144 0.19059 hCV32160712rs11079160 EO_STK REC TT 1.8 0.864 3.751 0.1167 — hCV32160712 rs11079160ISCHEMIC_STK ADD T 1.137 0.972 1.33 0.1085 — hCV32160712 rs11079160ISCHEMIC_STK AGE GEN TT 1.675 0.848 3.308 0.1373 0.31696 MALE DIAB HTNhCV32160712 rs11079160 ISCHEMIC_STK AGE REC TT 1.646 0.837 3.237 0.1488— MALE DIAB HTN hCV32160712 rs11079160 NOHD_STK GEN TT 1.509 0.886 2.570.1303 0.30893 hCV32160712 rs11079160 NOHD_STK REC TT 1.49 0.878 2.5310.1396 — hCV32160712 rs11079160 RECURRENT_STK GEN TT 1.887 0.865 4.1170.1107 0.28017 hCV32160712 rs11079160 RECURRENT_STK REC TT 1.87 0.8634.056 0.1128 — hCV32160712 rs11079160 RECURRENT_STK AGE GEN TT 2.0440.706 5.92 0.1878 0.41924 MALE DIAB HTN hCV32160712 rs11079160RECURRENT_STK AGE REC TT 2.029 0.706 5.827 0.1887 — MALE DIAB HTNhCV1408483 rs17070848 BCL2 ATHERO_STK GEN TT 1.514 0.894 2.564 0.12310.29337 hCV1408483 rs17070848 BCL2 ATHERO_STK REC TT 1.487 0.882 2.5050.1364 — hCV1619596 rs1048621 SDCBP2 CE_STK GEN AG 1.176 0.932 1.4830.1731 0.21433 hCV1619596 rs1048621 SDCBP2 CE_STK GEN AA 1.35 0.8882.055 0.1607 0.21433 hCV1619596 rs1048621 SDCBP2 CE_STK DOM AG or 1.2030.964 1.501 0.1025 — AA hCV1619596 rs1048621 SDCBP2 CE_STK AGE ADD A1.204 0.959 1.51 0.109 — MALE DIAB HTN hCV1619596 rs1048621 SDCBP2EO_STK AGE ADD A 1.202 0.965 1.497 0.101 — MALE DIAB HTN hCV1619596rs1048621 SDCBP2 ISCHEMIC_STK GEN AG 1.127 0.945 1.344 0.1838 0.22154hCV1619596 rs1048621 SDCBP2 ISCHEMIC_STK GEN AA 1.261 0.909 1.748 0.16440.22154 hCV1619596 rs1048621 SDCBP2 ISCHEMIC_STK DOM AG or 1.148 0.971.357 0.1079 — AA hCV1619596 rs1048621 SDCBP2 ISCHEMIC_STK AGE ADD A1.139 0.954 1.36 0.1508 — MALE DIAB HTN hCV1619596 rs1048621 SDCBP2NOHD_STK GEN AA 1.267 0.89 1.804 0.1884 0.27789 hCV1619596 rs1048621SDCBP2 NOHD_STK ADD A 1.125 0.974 1.299 0.1095 — hCV1619596 rs1048621SDCBP2 NOHD_STK DOM AG or 1.146 0.955 1.375 0.1442 — AA hCV1619596rs1048621 SDCBP2 NOHD_STK AGE GEN AG 1.217 0.944 1.569 0.1302 0.29766MALE DIAB HTN hCV1619596 rs1048621 SDCBP2 NOHD_STK AGE ADD A 1.14 0.9441.376 0.1722 — MALE DIAB HTN hCV1619596 rs1048621 SDCBP2 NOHD_STK AGEDOM AG or 1.21 0.951 1.541 0.1208 — MALE AA DIAB HTN hCV1619596rs1048621 SDCBP2 RECURRENT_STK GEN AG 1.23 0.896 1.689 0.1998 0.42372hCV1619596 rs1048621 SDCBP2 RECURRENT_STK DOM AG or 1.224 0.904 1.6580.1917 — AA hCV1619596 rs1048621 SDCBP2 RECURRENT_STK AGE GEN AG 1.3340.86 2.07 0.1987 0.41241 MALE DIAB HTN hCV29537898 rs6073804 NOHD_STKADD T 1.194 0.943 1.511 0.1415 — hCV29537898 rs6073804 RECURRENT_STK AGEGEN TT 5.809 0.6 56.26 0.1288 0.23964 MALE DIAB HTN hCV29537898rs6073804 RECURRENT_STK AGE REC TT 5.608 0.578 54.4 0.1369 — MALE DIABHTN hCV1723718 rs12481805 UMODL1 EO_STK REC AA 1.45 0.917 2.293 0.1118 —hCV1723718 rs12481805 UMODL1 ISCHEMIC_STK REC AA 1.254 0.922 1.7060.1498 — hCV1723718 rs12481805 UMODL1 LACUNAR_STK AGE REC AA 1.545 0.8382.848 0.1633 — MALE DIAB HTN hCV1723718 rs12481805 UMODL1 NOHD_STK RECAA 1.316 0.947 1.829 0.1019 — hCV1723718 rs12481805 UMODL1 NONCE_STK RECAA 1.33 0.945 1.872 0.1017 — hCV1723718 rs12481805 UMODL1 RECURRENT_STKAGE GEN AG 1.349 0.867 2.098 0.185 0.37072 MALE DIAB HTN hCV1723718rs12481805 UMODL1 RECURRENT_STK AGE ADD A 1.239 0.897 1.711 0.1934 —MALE DIAB HTN hCV1723718 rs12481805 UMODL1 RECURRENT_STK AGE DOM AG or1.352 0.889 2.056 0.159 — MALE AA DIAB HTN

TABLE 22 Gene GENO Risk hCV # rs # Symbol ENDPT MODE STRATA ADJUST TYPEGenotype hCV16336 r5362277 HD ENDPT4F1 GEN ALL STATIN TC CC hCV16336r5362277 HD ENDPT4F1 DOM ALL STATIN TC + TT CC hCV16336 r5362277 HDENDPT4F1 ADD ALL STATIN T CC hCV32160712 rs11079160 ENDPT4F1 GEN ALLSTATIN TT TT hCV32160712 rs11079160 ENDPT4F1 REC ALL STATIN TT TThCV32160712 rs11079160 ENDPT4F1 ADD ALL STATIN T TT hCV16134786r52857595 ENDPT4F1 REC ALL AA AA hCV1619596 rs1048621 SDCBP2 ENDPT4F1GEN ALL AA AG or AA hCV1619596 rs1048621 SDCBP2 ENDPT4F1 REC ALL AA AGor AA hCV32160712 rs11079160 ENDPT4F1 GEN ALL TT TT hCV32160712rs11079160 ENDPT4F1 DOM ALL TA + TT TT hCV32160712 rs11079160 ENDPT4F1REC ALL TT TT hCV32160712 rs11079160 ENDPT4F1 ADD ALL T TT 95% 95% LowerUpper CL fo r CL for P- 2DF P- hCV # rs # EVENTS TOTAL HR HR HR VALUEVALUE hCV16336 r5362277 21 491 0.7 0.444 1.115 0.1341 0.3256 hCV16336r5362277 23 526 0.72 0.462 1.12 0.1447 — hCV16336 r5362277 — — 0.760.507 1.14 0.1848 — hCV32160712 rs11079160 8 83 1.88 0.914 3.853 0.08660.221 hCV32160712 rs11079160 8 83 1.82 0.895 3.714 0.0981 — hCV32160712rs11079160 — — 1.21 0.918 1.604 0.1746 — hCV16134786 r52857595 5 45 1.920.778 4.735 0.1569 — hCV1619596 rs1048621 12 115 1.69 0.894 3.195 0.10650.1552 hCV1619596 rs1048621 12 115 1.78 0.97 3.274 0.0627 — hCV32160712rs11079160 6 37 3.09 1.33 7.19 0.0088 0.0281 hCV32160712 rs11079160 34428 1.41 0.917 2.164 0.1172 — hCV32160712 rs11079160 6 37 2.87 1.2536.585 0.0126 — hCV32160712 rs11079160 — — 1.48 1.037 2.12 0.0308 —

TABLE 23 95% 95% Lower Upper Gene GENO- Risk Risk CL for CL for P- hCV #rs # Symbol ENDPT TIMEVAR MODE TYPE Allele Genotype STATIN EVENTS TOTALHR HR HR VALUE PVAL_INTX hCV27830265 rs12762303 ALOX5 ENDPT4F1TIMETO_EP4F1 GEN GG G GA or GG Pravastatin 0 23 0 0 — 0.9967 0.15026hCV27830265 rs12762303 ALOX5 ENDPT4F1 TIMETO_EP4F1 GEN GG G GA or GGPlacebo 2 42 ref — — — 0.15026 hCV27830265 rs12762303 ALOX5 ENDPT4F1TIMETO_EP4F1 GEN GA G GA or GG Pravastatin 13 376 0.47 0.239 0.9060.0243 0.15026 hCV27830265 rs12762303 ALOX5 ENDPT4F1 TIMETO_EP4F1 GEN GAG GA or GG Placebo 26 351 ref — — — 0.15026 hCV27830265 rs12762303 ALOX5ENDPT4F1 TIMETO_EP4F1 GEN AA G GA or GG Pravastatin 54 1005 0.84 0.5841.212 0.3548 0.15026 hCV27830265 rs12762303 ALOX5 ENDPT4F1 TIMETO_EP4F1GEN AA G GA or GG Placebo 62 980 ref — — — 0.15026 hCV27830265rs12762303 ALOX5 ENDPT4F1 TIMETO_EP4F1 DOM GA + GG G GA or GGPravastatin 13 399 0.46 0.236 0.88 0.0192 0.10233 hCV27830265 rs12762303ALOX5 ENDPT4F1 TIMETO_EP4F1 DOM GA + GG G GA or GG Placebo 28 393 ref —— — 0.10233 hCV27830265 rs12762303 ALOX5 ENDPT4F1 TIMETO_EP4F1 REC GA +AA G GA or GG Pravastatin 67 1381 0.73 0.531 1.002 0.0514 0.24445hCV27830265 rs12762303 ALOX5 ENDPT4F1 TIMETO_EP4F1 REC GA + AA G GA orGG Placebo 88 1331 ref — — — 0.24445 hCV27830265 rs12762303 ALOX5ENDPT4F1 TIMETO_EP4F1 GEN GG G GA or GG Pravastatin 0 23 0 0 — 0.99670.15067 hCV27830265 rs12762303 ALOX5 ENDPT4F1 TIMETO_EP4F1 GEN GG G GAor GG Placebo 2 42 ref — — — 0.15067 hCV27830265 rs12762303 ALOX5ENDPT4F1 TIMETO_EP4F1 GEN GA G GA or GG Pravastatin 13 375 0.47 0.240.911 0.0254 0.15067 hCV27830265 rs12762303 ALOX5 ENDPT4F1 TIMETO_EP4F1GEN GA G GA or GG Placebo 26 352 ref — — — 0.15067 hCV27830265rs12762303 ALOX5 ENDPT4F1 TIMETO_EP4F1 GEN AA G GA or GG Pravastatin 541002 0.85 0.587 1.218 0.3671 0.15067 hCV27830265 rs12762303 ALOX5ENDPT4F1 TIMETO EP4F1 GEN AA G GA or GG Placebo 62 981 ref — — — 0.15067hCV27830265 rs12762303 ALOX5 ENDPT4F1 TIMETO_EP4F1 DOM GA + GG G GA orGG Pravastatin 13 398 0.46 0.237 0.884 0.02 0.10281 hCV27830265rs12762303 ALOX5 ENDPT4F1 TIMETO_EP4F1 DOM GA + GG G GA or GG Placebo 28394 ref — — — 0.10281 hCV27830265 rs12762303 ALOX5 ENDPT4F1 TIMETO_EP4F1REC GA + AA G GA or GG Pravastatin 67 1377 0.73 0.533 1.007 0.05490.24354 hCV27830265 rs12762303 ALOX5 ENDPT4F1 TIMETO_EP4F1 REC GA + AA GGA or GG Placebo 88 1333 ref — — — 0.24354 hCV8942032 rs1264352 DDR1ENDPT4F1 TIMETO_EP4F1 GEN CC C CG or CC Pravastatin 1 36 0.86 0.05413.71 0.9134 0.18029 hCV8942032 rs1264352 DDR1 ENDPT4F1 TIMETO_EP4F1 GENCC C CG or CC Placebo 1 31 ref — — — 0.18029 hCV8942032 rs1264352 DDR1ENDPT4F1 TIMETO_EP4F1 GEN CG C CG or CC Pravastatin 9 356 0.39 0.1790.844 0.0169 0.18029 hCV8942032 rs1264352 DDR1 ENDPT4F1 TIMETO_EP4F1 GENCG C CG or CC Placebo 22 347 ref — — — 0.18029 hCV8942032 rs1264352 DDR1ENDPT4F1 TIMETO_EP4F1 GEN GG C CG or CC Pravastatin 57 1011 0.84 0.5921.201 0.3442 0.18029 hCV8942032 rs1264352 DDR1 ENDPT4F1 TIMETO_EP4F1 GENGG C CG or CC Placebo 67 997 ref — — — 0.18029 hCV8942032 rs1264352 DDR1ENDPT4F1 TIMETO_EP4F1 DOM CG + CC C CG or CC Pravastatin 10 392 0.410.195 0.859 0.0182 0.07391 hCV8942032 rs1264352 DDR1 ENDPT4F1TIMETO_EP4F1 DOM CG + CC C CG or CC Placebo 23 378 ref — — — 0.07391hCV8942032 rs1264352 DDR1 ENDPT4F1 TIMETO_EP4F1 REC CG + GG C CG or CCPravastatin 66 1367 0.73 0.527 0.997 0.0479 0.92551 hCV8942032 rs1264352DDR1 ENDPT4F1 TIMETO_EP4F1 REC CG + GG C CG or CC Placebo 89 1344 ref —— — 0.92551 hCV16134786 rs2857595 ENDPT4F1 TIMETO_EP4F1 GEN ALL AA AAPravastatin 2 71 0.23 0.044 1.189 0.0794 0.27061 hCV16134786 rs2857595ENDPT4F1 TIMETO_EP4F1 GEN ALL AA AA Placebo 5 45 ref — — — 0.27061hCV16134786 rs2857595 ENDPT4F1 TIMETO_EP4F1 GEN ALL AG AA Pravastatin 14403 0.67 0.342 1.293 0.2295 0.27061 hCV16134786 rs2857595 ENDPT4F1TIMETO_EP4F1 GEN ALL AG AA Placebo 23 442 ref — — — 0.27061 hCV16134786rs2857595 ENDPT4F1 TIMETO_EP4F1 GEN ALL GG AA Pravastatin 51 928 0.80.553 1.164 0.2463 0.27061 hCV16134786 rs2857595 ENDPT4F1 TIMETO_EP4F1GEN ALL GG AA Placebo 61 887 ref — — — 0.27061 hCV16134786 rs2857595ENDPT4F1 TIMETO_EP4F1 DOM ALL AG + AA AA Pravastatin 16 474 0.58 0.3131.068 0.0803 0.35911 hCV16134786 rs2857595 ENDPT4F1 TIMETO_EP4F1 DOM ALLAG + AA AA Placebo 28 487 ref — — — 0.35911 hCV16134786 rs2857595ENDPT4F1 TIMETO_EP4F1 REC ALL AG + GG AA Pravastatin 65 1331 0.77 0.5591.068 0.1182 0.12065 hCV16134786 rs2857595 ENDPT4F1 TIMETO_EP4F1 REC ALLAG + GG AA Placebo 84 1329 ref — — — 0.12065 hCV1619596 rs1048621 SDCBP2ENDPT4F1 TIMETO_EP4F1 GEN ALL AA AG or AA Pravastatin 2 108 0.16 0.0370.734 0.018 0.05456 hCV1619596 rs1048621 SDCBP2 ENDPT4F1 TIMETO_EP4F1GEN ALL AA AG or AA Placebo 12 115 ref — — — 0.05456 hCV1619596rs1048621 SDCBP2 ENDPT4F1 TIMETO_EP4F1 GEN ALL AG AG or AA Pravastatin29 572 0.89 0.538 1.471 0.6494 0.05456 hCV1619596 rs1048621 SDCBP2ENDPT4F1 TIMETO_EP4F1 GEN ALL AG AG or AA Placebo 32 559 ref — — —0.05456 hCV1619596 rs1048621 SDCBP2 ENDPT4F1 TIMETO_EP4F1 GEN ALL GG AGor AA Pravastatin 36 719 0.77 0.498 1.197 0.2473 0.05456 hCV1619596rs1048621 SDCBP2 ENDPT4F1 TIMETO_EP4F1 GEN ALL GG AG or AA Placebo 45696 ref — — — 0.05456 hCV1619596 rs1048621 SDCBP2 ENDPT4F1 TIMETO_EP4F1DOM ALL AG + AA AG or AA Pravastatin 31 680 0.69 0.438 1.098 0.11880.74301 hCV1619596 rs1048621 SDCBP2 ENDPT4F1 TIMETO_EP4F1 DOM ALL AG +AA AG or AA Placebo 44 674 ref — — — 0.74301 hCV1619596 rs1048621 SDCBP2ENDPT4F1 TIMETO_EP4F1 REC ALL AG + GG AG or AA Pravastatin 65 1291 0.820.59 1.142 0.2405 0.01754 hCV1619596 rs1048621 SDCBP2 ENDPT4F1TIMETO_EP4F1 REC ALL AG + GG AG or AA Placebo 77 1255 ref — — — 0.01754hCV32160712 rs11079160 ENDPT4F1 TIMETO_EP4F1 GEN ALL TT TT Pravastatin 246 0.24 0.048 1.193 0.0812 0.22268 hCV32160712 rs11079160 ENDPT4F1TIMETO_EP4F1 GEN ALL TT TT Placebo 6 37 ref — — — 0.22268 hCV32160712rs11079160 ENDPT4F1 TIMETO_EP4F1 GEN ALL TA TT Pravastatin 17 382 0.620.339 1.132 0.1194 0.22268 hCV32160712 rs11079160 ENDPT4F1 TIMETO_EP4F1GEN ALL TA TT Placebo 28 391 ref — — — 0.22268 hCV32160712 rs11079160ENDPT4F1 TIMETO_EP4F1 GEN ALL AA TT Pravastatin 48 972 0.86 0.582 1.2670.4421 0.22268 hCV32160712 rs11079160 ENDPT4F1 TIMETO_EP4F1 GEN ALL AATT Placebo 54 942 ref — — — 0.22268 hCV32160712 rs11079160 ENDPT4F1TIMETO_EP4F1 DOM ALL TA + TT TT Pravastatin 19 428 0.55 0.315 0.9670.0379 0.20087 hCV32160712 rs11079160 ENDPT4F1 TIMETO_EP4F1 DOM ALL TA +TT TT Placebo 34 428 ref — — — 0.20087 hCV32160712 rs11079160 ENDPT4F1TIMETO_EP4F1 REC ALL TA + AA TT Pravastatin 65 1354 0.78 0.562 1.0770.1301 0.13978 hCV32160712 rs11079160 ENDPT4F1 TIMETO_EP4F1 REC ALL TA +AA TT Placebo 82 1333 ref — — — 0.13978

TABLE 24 Gene/ GENO- hCV # rs # Chrom ENDPT MODE ADJUST TYPE EVENTShCV1305848 rs6016200 ENDPT4F1 GEN STATIN AA 0 hCV1305848 rs6016200ENDPT4F1 GEN STATIN AG 41 hCV1305848 rs6016200 ENDPT4F1 GEN STATIN GG115 hCV1305848 rs6016200 ENDPT4F1 DOM STATIN AG + AA 41 hCV1305848rs6016200 ENDPT4F1 DOM STATIN GG 115 hCV1305848 rs6016200 ENDPT4F1 RECSTATIN AA 0 hCV1305848 rs6016200 ENDPT4F1 REC STATIN AG + GG 156hCV1305848 rs6016200 ENDPT4F1 ADD STATIN A — hCV1746715 rs4750628C10orf38 ENDPT4F1 GEN STATIN AA 39 hCV1746715 rs4750628 C10orf38ENDPT4F1 GEN STATIN AG 89 hCV1746715 rs4750628 C10orf38 ENDPT4F1 GENSTATIN GG 28 hCV1746715 rs4750628 C10orf38 ENDPT4F1 DOM STATIN AG + AA128 hCV1746715 rs4750628 C10orf38 ENDPT4F1 DOM STATIN GG 28 hCV1746715rs4750628 C10orf38 ENDPT4F1 REC STATIN AA 39 hCV1746715 rs4750628C10orf38 ENDPT4F1 REC STATIN AG + GG 117 hCV1746715 rs4750628 C10orf38ENDPT4F1 ADD STATIN A — hCV29881864 rs10514542 ENDPT4F1 GEN STATIN CC 20hCV29881864 rs10514542 ENDPT4F1 GEN STATIN CG 61 hCV29881864 rs10514542ENDPT4F1 GEN STATIN GG 75 hCV29881864 rs10514542 ENDPT4F1 DOM STATINCG + CC 81 hCV29881864 rs10514542 ENDPT4F1 DOM STATIN GG 75 hCV29881864rs10514542 ENDPT4F1 REC STATIN CC 20 hCV29881864 rs10514542 ENDPT4F1 RECSTATIN CG + GG 136 hCV29881864 rs10514542 ENDPT4F1 ADD STATIN C —hDV70959216 rs17482753 ENDPT4F1 GEN STATIN TT 0 hDV70959216 rs17482753ENDPT4F1 GEN STATIN TG 20 hDV70959216 rs17482753 ENDPT4F1 GEN STATIN GG136 hDV70959216 rs17482753 ENDPT4F1 DOM STATIN TG + TT 20 hDV70959216rs17482753 ENDPT4F1 DOM STATIN GG 136 hDV70959216 rs17482753 ENDPT4F1REC STATIN TT 0 hDV70959216 rs17482753 ENDPT4F1 REC STATIN TG + GG 156hDV70959216 rs17482753 ENDPT4F1 ADD STATIN T — hCV1305848 rs6016200ENDPT4F1 GEN AA 0 hCV1305848 rs6016200 ENDPT4F1 GEN AG 22 hCV1305848rs6016200 ENDPT4F1 GEN GG 67 hCV1305848 rs6016200 ENDPT4F1 DOM AG + AA22 hCV1305848 rs6016200 ENDPT4F1 DOM GG 67 hCV1305848 rs6016200 ENDPT4F1REC AA 0 hCV1305848 rs6016200 ENDPT4F1 REC AG + GG 89 hCV1305848rs6016200 ENDPT4F1 ADD A — hCV1746715 rs4750628 C10orf38 ENDPT4F1 GEN AA21 hCV1746715 rs4750628 C10orf38 ENDPT4F1 GEN AG 52 hCV1746715 rs4750628C10orf38 ENDPT4F1 GEN GG 16 hCV1746715 rs4750628 C10orf38 ENDPT4F1 DOMAG + AA 73 hCV1746715 rs4750628 C10orf38 ENDPT4F1 DOM GG 16 hCV1746715rs4750628 C10orf38 ENDPT4F1 REC AA 21 hCV1746715 rs4750628 C10orf38ENDPT4F1 REC AG + GG 68 hCV1746715 rs4750628 C10orf38 ENDPT4F1 ADD A —hCV29881864 rs10514542 ENDPT4F1 GEN CC 14 hCV29881864 rs10514542ENDPT4F1 GEN CG 35 hCV29881864 rs10514542 ENDPT4F1 GEN GG 40 hCV29881864rs10514542 ENDPT4F1 DOM CG + CC 49 hCV29881864 rs10514542 ENDPT4F1 DOMGG 40 hCV29881864 rs10514542 ENDPT4F1 REC CC 14 hCV29881864 rs10514542ENDPT4F1 REC CG + GG 75 hCV29881864 rs10514542 ENDPT4F1 ADD C — 95% 95%Lower Upper CL for CL for P- 2DF P- hCV # rs # TOTAL HR HR HR VALUEVALUE hCV1305848 rs6016200 86 0 0 1.63E+248 0.9648 0.2079 hCV1305848rs6016200 875 0.72 0.507 1.035 0.0764 0.2079 hCV1305848 rs6016200 1806ref — — — 0.2079 hCV1305848 rs6016200 961 0.66 0.46 0.938 0.0209 —hCV1305848 rs6016200 1806 ref — — — — hCV1305848 rs6016200 86 0 09.16E+246 0.9649 — hCV1305848 rs6016200 2681 ref — — — — hCV1305848rs6016200 — 0.63 0.451 0.876 0.0061 — hCV1746715 rs4750628 701 1.470.906 2.392 0.1187 0.0324 hCV1746715 rs4750628 1340 1.76 1.151 2.6910.0091 0.0324 hCV1746715 rs4750628 726 ref — — — 0.0324 hCV1746715rs4750628 2041 1.66 1.103 2.5 0.015 — hCV1746715 rs4750628 726 ref — — —— hCV1746715 rs4750628 701 0.99 0.688 1.42 0.9495 — hCV1746715 rs47506282066 ref — — — — hCV1746715 rs4750628 — 1.18 0.947 1.465 0.1424 —hCV29881864 rs10514542 224 1.76 1.072 2.875 0.0253 0.0767 hCV29881864rs10514542 1102 1.06 0.756 1.486 0.7354 0.0767 hCV29881864 rs105145421450 ref — — — 0.0767 hCV29881864 rs10514542 1326 1.18 0.858 1.6090.3138 — hCV29881864 rs10514542 1450 ref — — — — hCV29881864 rs10514542224 1.71 1.07 2.736 0.0249 — hCV29881864 rs10514542 2552 ref — — — —hCV29881864 rs10514542 — 1.24 0.975 1.564 0.08 — hDV70959216 rs1748275321 0 0 — 0.974 0.2331 hDV70959216 rs17482753 495 0.66 0.416 1.063 0.0880.2331 hDV70959216 rs17482753 2252 ref — — — 0.2331 hDV70959216rs17482753 516 0.64 0.399 1.019 0.0599 — hDV70959216 rs17482753 2252 ref— — — — hDV70959216 rs17482753 21 0 0 — 0.974 — hDV70959216 rs174827532747 ref — — — — hDV70959216 rs17482753 — 0.63 0.398 0.991 0.0458 —hCV1305848 rs6016200 44 0 0 . 0.9823 0.3016 hCV1305848 rs6016200 4260.68 0.422 1.107 0.1216 0.3016 hCV1305848 rs6016200 898 ref — — — 0.3016hCV1305848 rs6016200 470 0.62 0.381 0.997 0.0487 — hCV1305848 rs6016200898 ref — — — — hCV1305848 rs6016200 44 0 0 — 0.9823 — hCV1305848rs6016200 1324 ref — — — — hCV1305848 rs6016200 — 0.59 0.379 0.9290.0226 — hCV1746715 rs4750628 349 1.34 0.699 2.568 0.3775 0.1054hCV1746715 rs4750628 665 1.79 1.021 3.132 0.0421 0.1054 hCV1746715rs4750628 355 ref — — — 0.1054 hCV1746715 rs4750628 1014 1.63 0.95 2.8020.0763 — hCV1746715 rs4750628 355 ref — — — — hCV1746715 rs4750628 3490.89 0.545 1.449 0.6359 — hCV1746715 rs4750628 1020 ref — — — —hCV1746715 rs4750628 — 1.13 0.844 1.501 0.4216 — hCV29881864 rs10514542115 2.28 1.238 4.187 0.0081 0.0236 hCV29881864 rs10514542 565 1.06 0.6751.673 0.7927 0.0236 hCV29881864 rs10514542 694 ref — — — 0.0236hCV29881864 rs10514542 680 1.25 0.826 1.903 0.2888 — hCV29881864rs10514542 694 ref — — — — hCV29881864 rs10514542 115 2.21 1.25 3.9210.0064 — hCV29881864 rs10514542 1259 ref — — — — hCV29881864 rs10514542— 1.38 1.009 1.878 0.0438 —

TABLE 25 Gene GENO- Risk hCV # rs # Symbol ENDPT TIMEVAR MODE TYPEAllele STATIN hDV77718013 ENDPT4F1 TIMETO_EP4F1 REC TC + CC PravastatinhCV3216551 rs562338 ENDPT4F1 TIMETO_EP4F1 GEN GG Pravastatin hCV2862873rs780094 GCKR ENDPT4F1 TIMETO_EP4F1 DOM TC + TT Pravastatin hCV9296529rs4358307 ENDPT4F1 TIMETO_EP4F1 GEN GA Pravastatin hCV29480044rs10516433 TSPAN5 ENDPT4F1 TIMETO_EP4F1 GEN TC Pravastatin hCV29480044rs10516433 TSPAN5 ENDPT4F1 TIMETO_EP4F1 REC TC + CC PravastatinhCV30454150 rs10516434 TSPAN5 ENDPT4F1 TIMETO_EP4F1 GEN TC PravastatinhCV30454150 rs10516434 TSPAN5 ENDPT4F1 TIMETO_EP4F1 REC TC + CCPravastatin hCV8942032 rs1264352 DDR1 ENDPT4F1 TIMETO_EP4F1 DOM CG + CCC Pravastatin hCV9473891 rs1555173 ENDPT4F1 TIMETO_EP4F1 REC CT + TTPravastatin hCV2442143 rs12544854 ASAH1 ENDPT4F1 TIMETO_EP4F1 GEN TCPravastatin hCV2442143 rs12544854 ASAH1 ENDPT4F1 TIMETO_EP4F1 DOM TC +TT Pravastatin hCV2442143 rs12544854 ASAH1 ENDPT4F1 TIMETO_EP4F1 GEN TCPravastatin hCV2442143 rs12544854 ASAH1 ENDPT4F1 TIMETO_EP4F1 DOM TC +TT Pravastatin hCV1463226 rs10890 FXN ENDPT4F1 TIMETO_EP4F1 GEN TTPravastatin hCV1463226 rs10890 FXN ENDPT4F1 TIMETO_EP4F1 GEN CCPravastatin hCV2741051 rs2230806 ABCA1 ENDPT4F1 TIMETO_EP4F1 GEN TCPravastatin hCV2741051 rs2230806 ABCA1 ENDPT4F1 TIMETO_EP4F1 DOM TC + TTPravastatin hCV2741051 rs2230806 ABCA1 ENDPT4F1 TIMETO_EP4F1 GEN TCPravastatin hCV2741051 rs2230806 ABCA1 ENDPT4F1 TIMETO_EP4F1 DOM TC + TTPravastatin hCV2959482 rs3890182 ABCA1 ENDPT4F1 TIMETO_EP4F1 GEN AGPravastatin hCV2959482 rs3890182 ABCA1 ENDPT4F1 TIMETO_EP4F1 DOM AG + AAPravastatin hCV22275299 rs28927680 BUD13 ENDPT4F1 TIMETO_EP4F1 GEN GCPravastatin hCV29566897 rs10507755 ENDPT4F1 TIMETO_EP4F1 REC CT + TTPravastatin hCV8757333 rs1800588 LIPC ENDPT4F1 TIMETO_EP4F1 DOM TC + TTPravastatin hCV16164743 rs2928932 ENDPT4F1 TIMETO_EP4F1 GEN CCPravastatin hCV16164743 rs2928932 ENDPT4F1 TIMETO_EP4F1 GEN AAPravastatin hCV9324316 rs9305020 ENDPT4F1 TIMETO_EP4F1 GEN TTPravastatin hCV9324316 rs9305020 ENDPT4F1 TIMETO_EP4F1 REC CT + TTPravastatin hCV1846459 rs4803759 ENDPT4F1 TIMETO_EP4F1 GEN TCPravastatin hCV1846459 rs4803759 ENDPT4F1 TIMETO_EP4F1 GEN CCPravastatin hCV1846459 rs4803759 ENDPT4F1 TIMETO_EP4F1 REC TC + CCPravastatin hCV26682080 rs4420638 ENDPT4F1 TIMETO_EP4F1 GEN GGPravastatin hCV26682080 rs4420638 ENDPT4F1 TIMETO_EP4F1 GEN GAPravastatin hCV26682080 rs4420638 ENDPT4F1 TIMETO_EP4F1 DOM GA + GGPravastatin 95% 95% Lower Upper CL for CL for P- hCV # rs # EVENTS TOTALHR HR HR VALUE PVAL_INTX hDV77718013 66 1359 0.74 0.539 1.022 0.06730.0556 hCV3216551 rs562338 40 932 0.59 0.401 0.877 0.0089 0.04137hCV2862873 rs780094 41 887 0.6 0.403 0.881 0.0095 0.09031 hCV9296529rs4358307 25 624 0.5 0.307 0.807 0.0047 0.08098 hCV29480044 rs1051643316 454 0.46 0.255 0.832 0.0101 0.03925 hCV29480044 rs10516433 61 13090.67 0.487 0.934 0.0178 0.04698 hCV30454150 rs10516434 16 451 0.46 0.2550.832 0.0102 0.04149 hCV30454150 rs10516434 61 1310 0.67 0.486 0.9310.017 0.04884 hCV8942032 rs1264352 10 392 0.41 0.195 0.859 0.01820.07391 hCV9473891 rs1555173 67 1363 0.75 0.547 1.035 0.0801 0.07415hCV2442143 rs12544854 29 713 0.55 0.35 0.877 0.0118 0.02918 hCV2442143rs12544854 43 1070 0.57 0.391 0.836 0.004 0.00824 hCV2442143 rs1254485429 704 0.57 0.36 0.905 0.0172 0.04882 hCV2442143 rs12544854 42 1059 0.560.384 0.825 0.0033 0.01402 hCV1463226 rs10890 9 303 0.41 0.188 0.8850.0233 0.02602 hCV1463226 rs10890 16 416 0.48 0.266 0.874 0.0162 0.02602hCV2741051 rs2230806 16 597 0.47 0.258 0.856 0.0136 0.09085 hCV2741051rs2230806 20 709 0.47 0.272 0.801 0.0056 0.03067 hCV2741051 rs2230806 17603 0.5 0.275 0.892 0.0192 0.06908 hCV2741051 rs2230806 20 711 0.470.273 0.802 0.0057 0.02439 hCV2959482 rs3890182 8 302 0.34 0.152 0.7670.0093 0.06769 hCV2959482 rs3890182 8 320 0.34 0.151 0.753 0.00810.02862 hCV22275299 rs28927680 2 175 0.2 0.042 0.908 0.0372 0.0983hCV29566897 rs10507755 67 1350 0.76 0.552 1.049 0.0957 0.02347hCV8757333 rs1800588 21 567 0.49 0.286 0.824 0.0074 0.05012 hCV16164743rs2928932 6 190 0.31 0.124 0.797 0.0148 0.03514 hCV16164743 rs2928932 23555 0.6 0.355 1.004 0.052 0.03514 hCV9324316 rs9305020 48 963 0.7 0.4821.016 0.0604 0.05765 hCV9324316 rs9305020 67 1352 0.76 0.554 1.05 0.09680.02527 hCV1846459 rs4803759 25 565 0.62 0.378 1.023 0.0613 0.05544hCV1846459 rs4803759 31 707 0.66 0.415 1.036 0.0707 0.05544 hCV1846459rs4803759 56 1272 0.64 0.457 0.895 0.0092 0.01624 hCV26682080 rs44206382 58 0.25 0.05 1.217 0.0855 0.07632 hCV26682080 rs4420638 15 383 0.50.268 0.919 0.0259 0.07632 hCV26682080 rs4420638 17 441 0.45 0.255 0.8040.0068 0.04158

TABLE 26 95% 95% Lower Upper GENO- CL for CL for P- hCV # rs # Gene MODESTRATA ADJUST TYPE EVENTS TOTAL HR HR HR VALUE hCV11474611 rs3814843CALM1 GEN ALL STATIN GG 1 3 7.54 1.055 53.886 0.0441 hCV11474611rs3814843 CALM1 GEN ALL STATIN GT 14 224 1.17 0.676 2.038 0.5698hCV11474611 rs3814843 CALM1 GEN ALL STATIN TT 128 2392 ref — — —hCV11474611 rs3814843 CALM1 REC ALL STATIN GG 1 3 7.43 1.041 53.0620.0455 hCV11474611 rs3814843 CALM1 REC ALL STATIN GT + TT 142 2616 ref —— — hCV11474611 rs3814843 CALM1 GEN ALL GG 1 3 6.64 0.919 47.944 0.0606hCV11474611 rs3814843 CALM1 GEN ALL GT 6 104 0.95 0.413 2.188 0.9051hCV11474611 rs3814843 CALM1 GEN ALL TT 70 1183 ref — — — hCV11474611rs3814843 CALM1 REC ALL GG 1 3 6.67 0.924 48.09 0.0599 hCV11474611rs3814843 CALM1 REC ALL GT + TT 76 1287 ref — — — hCV2930693 rs13183672FSTL4 REC ALL STATIN AA 96 1498 1.51 1.07 2.14 0.0191 hCV2930693rs13183672 FSTL4 REC ALL STATIN AC + CC 48 1122 ref — — — hCV2930693rs13183672 FSTL4 ADD ALL STATIN A — — 1.29 0.965 1.719 0.0859 hCV2930693rs13183672 FSTL4 REC ALL AA 52 729 1.61 0.998 2.59 0.0512 hCV2930693rs13183672 FSTL4 REC ALL AC + CC 25 560 ref — — — hCV2930693 rs13183672FSTL4 ADD ALL A — — 1.48 0.982 2.24 0.0609

TABLE 27 95% 95% Lower Upper GENO- CL for CL for P- hCV # rs Gene MODETYPE STATIN EVENTS TOTAL HR HR HR VALUE PVAL_INTX hCV1022614 rs220479ITGAE GEN CC Pravastatin 52 973 0.89 0.609 1.295 0.5366 0.22592hCV1022614 rs220479 ITGAE GEN CC Placebo 56 927 ref — — — 0.22592hCV1022614 rs220479 ITGAE GEN CT Pravastatin 15 408 0.48 0.257 0.8870.0192 0.22592 hCV1022614 rs220479 ITGAE GEN CT Placebo 30 400 ref — — —0.22592 hCV1022614 rs220479 ITGAE GEN TT Pravastatin 3 46 0.91 0.2034.047 0.8969 0.22592 hCV1022614 rs220479 ITGAE GEN TT Placebo 4 56 ref —— — 0.22592 hCV1022614 rs220479 ITGAE DOM CT + CC Pravastatin 67 13810.74 0.541 1.024 0.0696 0.79081 hCV1022614 rs220479 ITGAE DOM CT + CCPlacebo 86 1327 ref — — — 0.79081 hCV1022614 rs220479 ITGAE REC CT + TTPravastatin 18 454 0.52 0.294 0.921 0.0248 0.11998 hCV1022614 rs220479ITGAE REC CT + TT Placebo 34 456 ref — — — 0.11998 hCV11450563 rs2038366GEN GG Pravastatin 29 539 1.15 0.669 1.975 0.6132 0.17234 hCV11450563rs2038366 GEN GG Placebo 24 522 ref — — — 0.17234 hCV11450563 rs2038366GEN GT Pravastatin 28 638 0.61 0.381 0.986 0.0436 0.17234 hCV11450563rs2038366 GEN GT Placebo 43 602 ref — — — 0.17234 hCV11450563 rs2038366GEN TT Pravastatin 10 151 1.13 0.472 2.724 0.7789 0.17234 hCV11450563rs2038366 GEN TT Placebo 10 167 ref — — — 0.17234 hCV11450563 rs2038366DOM GT + GG Pravastatin 57 1177 0.81 0.567 1.148 0.2334 0.47195hCV11450563 rs2038366 DOM GT + GG Placebo 67 1124 ref — — — 0.47195hCV11450563 rs2038366 REC GT + TT Pravastatin 38 789 0.7 0.463 1.0640.0954 0.15155 hCV11450563 rs2038366 REC GT + TT Placebo 53 769 ref — —— 0.15155 hCV2091644 rs1010 VAMP8 GEN CC Pravastatin 12 271 1.18 0.512.73 0.6997 0.48071 hCV2091644 rs1010 VAMP8 GEN CC Placebo 10 258 ref —— — 0.48071 hCV2091644 rs1010 VAMP8 GEN CT Pravastatin 31 686 0.66 0.4181.045 0.0763 0.48071 hCV2091644 rs1010 VAMP8 GEN CT Placebo 45 666 ref —— — 0.48071 hCV2091644 rs1010 VAMP8 GEN TT Pravastatin 26 455 0.71 0.431.186 0.1928 0.48071 hCV2091644 rs1010 VAMP8 GEN TT Placebo 35 448 ref —— — 0.48071 hCV2091644 rs1010 VAMP8 DOM CT + CC Pravastatin 43 957 0.760.507 1.126 0.1678 0.87535 hCV2091644 rs1010 VAMP8 DOM CT + CC Placebo55 924 ref — — — 0.87535 hCV2091644 rs1010 VAMP8 REC CT + TT Pravastatin57 1141 0.68 0.487 0.961 0.0284 0.23503 hCV2091644 rs1010 VAMP8 REC CT +TT Placebo 80 1114 ref — — — 0.23503 hCV2169762 rs1804689 HPS1 GEN TTPravastatin 4 107 0.99 0.266 3.694 0.9903 0.34901 hCV2169762 rs1804689HPS1 GEN TT Placebo 5 131 ref — — — 0.34901 hCV2169762 rs1804689 HPS1GEN TG Pravastatin 36 652 0.92 0.583 1.468 0.7398 0.34901 hCV2169762rs1804689 HPS1 GEN TG Placebo 36 600 ref — — — 0.34901 hCV2169762rs1804689 HPS1 GEN GG Pravastatin 30 668 0.59 0.372 0.924 0.0214 0.34901hCV2169762 rs1804689 HPS1 GEN GG Placebo 49 651 ref — — — 0.34901hCV2169762 rs1804689 HPS1 DOM TG + TT Pravastatin 40 759 0.95 0.6121.461 0.8004 0.13433 hCV2169762 rs1804689 HPS1 DOM TG + TT Placebo 41731 ref — — — 0.13433 hCV2169762 rs1804689 HPS1 REC TG + GG Pravastatin66 1320 0.73 0.529 1.006 0.0547 0.65359 hCV2169762 rs1804689 HPS1 RECTG + GG Placebo 85 1251 ref — — — 0.65359 hCV2192261 rs3213646 EXOD1 GENCC Pravastatin 27 417 1.05 0.613 1.799 0.8592 0.20384 hCV2192261rs3213646 EXOD1 GEN CC Placebo 26 416 ref — — — 0.20384 hCV2192261rs3213646 EXOD1 GEN CT Pravastatin 24 691 0.54 0.328 0.898 0.01750.20384 hCV2192261 rs3213646 EXOD1 GEN CT Placebo 41 646 ref — — —0.20384 hCV2192261 rs3213646 EXOD1 GEN TT Pravastatin 13 245 0.64 0.3161.278 0.2036 0.20384 hCV2192261 rs3213646 EXOD1 GEN TT Placebo 20 243ref — — — 0.20384 hCV2192261 rs3213646 EXOD1 DOM CT + CC Pravastatin 511108 0.73 0.506 1.048 0.0882 0.72432 hCV2192261 rs3213646 EXOD1 DOM CT +CC Placebo 67 1062 ref — — — 0.72432 hCV2192261 rs3213646 EXOD1 REC CT +TT Pravastatin 37 936 0.57 0.379 0.857 0.007 0.07855 hCV2192261rs3213646 EXOD1 REC CT + TT Placebo 61 889 ref — — — 0.07855 hCV7425232rs3900940 MYH15 GEN CC Pravastatin 13 160 1.03 0.461 2.296 0.94480.57268 hCV7425232 rs3900940 MYH15 GEN CC Placebo 11 142 ref — — —0.57268 hCV7425232 rs3900940 MYH15 GEN CT Pravastatin 23 561 0.61 0.3651.022 0.0604 0.57268 hCV7425232 rs3900940 MYH15 GEN CT Placebo 39 583ref — — — 0.57268 hCV7425232 rs3900940 MYH15 GEN TT Pravastatin 30 6200.71 0.442 1.146 0.1618 0.57268 hCV7425232 rs3900940 MYH15 GEN TTPlacebo 39 573 ref — — — 0.57268 hCV7425232 rs3900940 MYH15 DOM CT + CCPravastatin 36 721 0.72 0.468 1.102 0.1293 0.97544 hCV7425232 rs3900940MYH15 DOM CT + CC Placebo 50 725 ref — — — 0.97544 hCV7425232 rs3900940MYH15 REC CT + TT Pravastatin 53 1181 0.66 0.467 0.939 0.0207 0.33623hCV7425232 rs3900940 MYH15 REC CT + TT Placebo 78 1156 ref — — — 0.33623hCV945276 rs89962 KRT4 GEN TT Pravastatin 9 238 0.96 0.392 2.375 0.93810.71864 hCV945276 rs89962 KRT4 GEN TT Placebo 10 255 ref — — — 0.71864hCV945276 rs89962 KRT4 GEN TG Pravastatin 37 674 0.64 0.423 0.979 0.03970.71864 hCV945276 rs89962 KRT4 GEN TG Placebo 53 628 ref — — — 0.71864hCV945276 rs89962 KRT4 GEN GG Pravastatin 17 443 0.65 0.349 1.196 0.16410.71864 hCV945276 rs89962 KRT4 GEN GG Placebo 25 426 ref — — — 0.71864hCV945276 rs89962 KRT4 DOM TG + TT Pravastatin 46 912 0.7 0.48 1.0270.0683 0.83505 hCV945276 rs89962 KRT4 DOM TG + TT Placebo 63 883 ref — —— 0.83505 hCV945276 rs89962 KRT4 REC TG + GG Pravastatin 54 1117 0.650.458 0.916 0.0141 0.42005 hCV945276 rs89962 KRT4 REC TG + GG Placebo 781054 ref — — — 0.42005

TABLE 28 Association of MYH15 (rs3900940/hCV7425232) with strokeendpoint in CARE Study population: CARE study (n = 2913) Endpoint:stroke or TIA (offical CARE endpoint) (“endpt4f1”) Statistical method:Cox model Association of MYH15 SNP (rs3900940/hCV7425232) with strokeendpoint in CARE combined treatment arms Adjusted1 Adjusted2 Adjusted3Genotype HR 95% CI 2-sided p-value HR 95% CI 2-sided p-value HR 95% CI2-sided p-value Hom_CC 1.403 0.88-2.23 0.153 1.51 0.94-2.40 0.086 1.490.93-2.37 0.094 Het_CT 0.925 0.66-1.30 0.6565 0.89 0.63-1.25 0.49 0.8810.62-1.24 0.4715 Maj_TT 1 1 1 Rec_CC 1.46 0.94-2.25 0.09 1.6 1.03-2.470.0358 1.58 1.02-2.45 0.039 Maj + het 1 1 1 “Adjusted1” = Adjusted forstatin use “Adjusted2” = Adjusted for traditional risk factors (TRF),body mass index (BMI), and statin use “Adjusted3” = Adjusted for TRF,BMI, statin use, and CHD (CARE primary endpoint) Conclusions: 1) TheMYH15 SNP (rs3900940/hCV7425232) was associated with stroke in CARE. 2)The MYH15 SNP (rs3900940/hCV7425232) was associated with stroke in CAREeven after adjusting for CHD. (CHD defined in accordance with CAREoriginal endpoint-fatal CHD/definite non-fatal MI, “endpt1”)

TABLE 29 Gene Risk GENO_ EVENTS_ TOTAL_ hCV # rs # symbol Allele MODESTRATA PLACEBO PLACEBO PLACEBO hCV2091644 rs1010   VAMP8 C GEN ALL CC 49521 hCV2091644 rs1010   VAMP8 C GEN hist CC 28 235 hCV2091644 rs1010  VAMP8 C GEN hist CT 58 633 hCV2442143 rs12544854 ASAH1 T GEN no hist CT48 808 hCV8942032 rs1264352  DDR1 C GEN ALL CC  8 110 hCV2169762rs1804689  HP51 T GEN no hist GT 38 670 hCV16158671 rs2200733  C4 T GENALL CT 37 489 hCV16158671 rs2200733  C4 T GEN no hist CT 19 285hCV16158671 rs2200733  C4 T GEN hist TT  3  10 hCV27504565 rs3219489 MUTYH C GEN hist CG 35 465 hCV27511436 rs3750145  FZD1 T GEN ALL CC  4 77 hCV27511436 rs3750145  FZD1 T GEN hist CC  1  31 hCV7425232rs3900940  MYH15 C GEN hist CT 55 528 HR_ LOWER_ UPPER_ P_ EVENTS_ nohCV # PLACEBO PLACEBO PLACEBO PLACEBO ALL event HR_ALL P_ALL hCV20916441.50982 1.030611 2.211844 0.0344528 88 951 1.340598 0.051104903hCV2091644 1.503 0.897908 2.515874 0.1210805 54 428 1.633661 0.014183695hCV2091644 1.13938 0.733208 1.770572 0.5617921 118 1136 1.3449790.076364852 hCV2442143 1.31132 0.778332 2.209298 0.3085018 101 15351.326084 0.166536479 hCV8942032 1.01239 0.495766 2.067369 0.9730365 22214 1.368996 0.190221586 hCV2169762 0.99636 0.64971 1.527967 0.986667885 1236 1.35397  0.062193717 hCV16158671 1.07497 0.753308 1.5339750.6902781 80 900 1.197273 0.172251195 hCV16158671 1.2283 0.7424712.032018 0.4233603 38 517 1.282126 0.189409128 hCV16158671 3.711451.175206 11.72124 0.0254095 4 18 2.311594 0.124212946 hCV275045650.70803 0.473602 1.0585 0.092402 69 853 0.726379 0.040276813 hCV275114360.65977 0.244625 1.779435 0.4113489 6 149 0.503156 0.113669409hCV27511436 0.32028 0.044599 2.300102 0.2576826 2 64 0.3072920.120384642 hCV7425232 1.21122 0.833465 1.760195 0.3149935 107 9561.224954 0.171949776

TABLE 30 Gene/ Chrom Risk GENO_ EVENTS_ TOTAL_ hCV # rs # symbol AlleleMODE STRATA PLACEBO PLACEBO PLACEBO hCV2091644 rs1010   VAMP8 C GEN ALLCC 49 521 hCV2091644 rs1010   VAMP8 C DOM ALL CC + CT 153  1968 hCV2091644 rs1010   VAMP8 C GEN no hist CC 21 286 hCV2091644 rs1010  VAMP8 C GEN hist CC 28 235 hCV26505812 rs10757274 C9p21 G GEN ALL AG121  1455  hCV26505812 rs10757274 C9p21 G DOM ALL GG + AG 169  2156 hCV26505812 rs10757274 C9p21 G GEN no hist GG 23 364 hCV26505812rs10757274 C9p21 G GEN no hist AG 52 826 hCV26505812 rs10757274 C9p21 GDOM no hist GG + AG 75 1190  hCV26505812 rs10757274 C9p21 G GEN hist AG69 629 hCV2442143 rs12544854 ASAH1 T GEN no hist TT 26 393 hCV8942032rs1264352  DDR1 C GEN no hist CG 37 550 hCV8942032 rs1264352  DDR1 C DOMno hist CC + CG 41 616 hCV16158671 rs2200733  C4 T GEN hist TT  3  10hCV27504565 rs3219489  MUTYH C GEN hist CG 35 465 hCV27504565 rs3219489 MUTYH C DOM hist GG + CG 41 523 hCV27511436 rs3750145  FZD1 T DOM ALLCC + CT 50 804 hCV27511436 rs3750145  FZD1 T GEN no hist CT 16 414hCV27511436 rs3750145  FZD1 T DOM no hist CC + CT 19 460 HR_ LOWER_UPPER_ P_ EVENTS_ no hCV # PLACEBO PLACEBO PLACEBO PLACEBO ALL eventHR_ALL P_ALL hCV2091644 1.509818 1.030611 2.211844 0.0344528 88 9511.340598 0.0511049 hCV2091644 1.242162 0.916407 1.683713 0.1622853hCV2091644 1.452091 0.820968 2.568392 0.1998539 34 523 1.0339620.91230651 hCV2091644 1.503005 0.897908 2.515874 0.1210805 54 4281.633661 0.0141837 hCV26505812 1.464442 1.027673 2.086842 0.0347703 2152683 1.118574 0.41790129 hCV26505812 1.381146 0.981881 1.9427660.0636069 hCV26505812 1.507129 0.820845 2.767193 0.1857813 47 6741.215134 0.39336777 hCV26505812 1.482778 0.876794 2.50758 0.1417039 871528 0.992161 1 hCV26505812 1.489002 0.900117 2.463154 0.1210931hCV26505812 1.372228 0.849193 2.217411 0.196237 128 1155 1.1858010.35086569 hCV2442143 1.479057 0.825673 2.649487 0.1881955 41 7041.173733 0.49295851 hCV8942032 1.324522 0.870367 2.015654 0.1895578 61972 1.10852 0.55960326 hCV8942032 1.305687 0.868558 1.962816 0.1996948hCV16158671 3.711451 1.175206 11.72124 0.0254095 4 18 2.3115940.12421295 hCV27504565 0.708031 0.473602 1.0585 0.092402 69 853 0.7263790.04027681 hCV27504565 0.741641 0.506363 1.08624 0.1247589 hCV275114360.80098 0.583058 1.100353 0.1707752 hCV27511436 0.603398 0.3517221.035162 0.066584 42 805 0.824734 0.33847297 hCV27511436 0.6460020.390525 1.068608 0.0888378

TABLE 31 Gene/ Chrom Risk GENO_ EVENTS_ hCV # rs # symbol Allele MODESTRATA RESP STATIN RESP hCV2091644 rs1010   VAMP8 C DOM no hist CC + CTpravastatin 50 hCV2091644 rs1010   VAMP8 C DOM no hist CC + CT placebo67 hCV29539757 rs10110659 KCNQ3 C REC hist CC + AC pravastatin 106 hCV29539757 rs10110659 KCNQ3 C REC hist CC + AC placebo 100  hCV26505812rs10757274 C9p21 G GEN ALL GG pravastatin 51 hCV26505812 rs10757274C9p21 G GEN ALL GG placebo 48 hCV26505812 rs10757274 C9p21 G GEN ALL AGpravastatin 94 hCV26505812 rs10757274 C9p21 G GEN ALL AG placebo 121 hCV26505812 rs10757274 C9p21 G GEN ALL AA pravastatin 56 hCV26505812rs10757274 C9p21 G GEN ALL AA placebo 41 hCV26505812 rs10757274 C9p21 GDOM ALL GG + AG pravastatin 145  hCV26505812 rs10757274 C9p21 G DOM ALLGG + AG placebo 169  hCV26505812 rs10757274 C9p21 G GEN no hist GGpravastatin 24 hCV26505812 rs10757274 C9p21 G GEN no hist GG placebo 23hCV26505812 rs10757274 C9p21 G GEN no hist AG pravastatin 35 hCV26505812rs10757274 C9p21 G GEN no hist AG placebo 52 hCV26505812 rs10757274C9p21 G GEN no hist AA pravastatin 28 hCV26505812 rs10757274 C9p21 G GENno hist AA placebo 19 hCV26505812 rs10757274 C9p21 G DOM no hist GG + AGpravastatin 59 hCV26505812 rs10757274 C9p21 G DOM no hist GG + AGplacebo 75 hCV2169762 rs1804689  HPS1 T DOM no hist TT + GT pravastatin57 hCV2169762 rs1804689  HPS1 T DOM no hist TT + GT placebo 47hCV2169762 rs1804689  HPS1 T REC hist GG + GT pravastatin 109 hCV2169762 rs1804689  HPS1 T REC hist GG + GT placebo 102  no TOTAL_LOWER_ UPPER_ P_INT_ hCV # event RESP HR_RESP RESP RESP P_RESP RESPhCV2091644 994 1044 0.7860368 0.54496 1.13377 0.19768 0.0837336hCV2091644 1033 1100 0.0837336 hCV29539757 1087 1193 1.0088023 0.767611.32578 0.94987 0.0530448 hCV29539757 1040 1140 0.0530448 hCV26505812638 689 1.0816406 0.7293 1.60421 0.69635 0.0696553 hCV26505812 653 7010.0696553 hCV26505812 1349 1443 0.7768621 0.59335 1.01713 0.066290.0696553 hCV26505812 1334 1455 0.0696553 hCV26505812 674 730 1.33049850.88923 1.99075 0.16486 0.0696553 hCV26505812 680 721 0.0696553hCV26505812 1987 2132 0.8638087 0.69193 1.07838 0.1959 0.0630809hCV26505812 1987 2156 0.0630809 hCV26505812 333 357 1.0681052 0.60281.89259 0.82141 0.0828923 hCV26505812 341 364 0.0828923 hCV26505812 754789 0.6977172 0.45454 1.071 0.09971 0.0828923 hCV26505812 774 8260.0828923 hCV26505812 395 423 1.5704654 0.87695 2.81243 0.128940.0828923 hCV26505812 424 443 0.0828923 hCV26505812 1087 1146 0.81318880.57817 1.14374 0.23474 0.0573322 hCV26505812 1115 1190 0.0573322hCV2169762 731 788 1.2655756 0.86016 1.86208 0.23193 0.033 hCV2169762777 824 0.033 hCV2169762 1063 1172 1.0276801 0.7845 1.34624 0.842890.0507564 hCV2169762 1035 1137 0.0507564

TABLE 32 Gene/ Chrom Risk GENO_ EVENTS_ hCV # rs # symbol Allele MODESTRATA RESP STATIN RESP hCV2091644 rs1010   VAMP8 C GEN no hist CCpravastatin 13 hCV2091644 rs1010   VAMP8 C GEN no hist CC placebo 21hCV2091644 rs1010   VAMP8 C GEN no hist CT pravastatin 37 hCV2091644rs1010   VAMP8 C GEN no hist CT placebo 46 hCV2091644 rs1010   VAMP8 CGEN no hist TT pravastatin 36 hCV2091644 rs1010   VAMP8 C GEN no hist TTplacebo 27 hCV2091644 rs1010   VAMP8 C DOM no hist CC + CT pravastatin50 hCV2091644 rs1010   VAMP8 C DOM no hist CC + CT placebo 67hCV29539757 rs10110659 KCNQ3 C GEN hist AA pravastatin 7 hCV29539757rs10110659 KCNQ3 C GEN hist AA placebo 16 hCV29539757 rs10110659 KCNQ3 CGEN hist AC pravastatin 44 hCV29539757 rs10110659 KCNQ3 C GEN hist ACplacebo 44 hCV29539757 rs10110659 KCNQ3 C GEN hist CC pravastatin 62hCV29539757 rs10110659 KCNQ3 C GEN hist CC placebo 56 hCV29539757rs10110659 KCNQ3 C REC hist CC + AC pravastatin 106 hCV29539757rs10110659 KCNQ3 C REC hist CC + AC placebo 100 hCV26505812 rs10757274C9p21 G GEN ALL GG pravastatin 51 hCV26505812 rs10757274 C9p21 G GEN ALLGG placebo 48 hCV26505812 rs10757274 C9p21 G GEN ALL AG pravastatin 94hCV26505812 rs10757274 C9p21 G GEN ALL AG placebo 121 hCV26505812rs10757274 C9p21 G GEN ALL AA pravastatin 56 hCV26505812 rs10757274C9p21 G GEN ALL AA placebo 41 hCV26505812 rs10757274 C9p21 G DOM ALLGG + AG pravastatin 145 hCV26505812 rs10757274 C9p21 G DOM ALL GG + AGplacebo 169 hCV26505812 rs10757274 C9p21 G GEN no hist GG pravastatin 24hCV26505812 rs10757274 C9p21 G GEN no hist GG placebo 23 hCV26505812rs10757274 C9p21 G GEN no hist AG pravastatin 35 hCV26505812 rs10757274C9p21 G GEN no hist AG placebo 52 hCV26505812 rs10757274 C9p21 G GEN nohist AA pravastatin 28 hCV26505812 rs10757274 C9p21 G GEN no hist AAplacebo 19 hCV26505812 rs10757274 C9p21 G DOM no hist GG + AGpravastatin 59 hCV26505812 rs10757274 C9p21 G DOM no hist GG + AGplacebo 75 hCV2442143 rs12544854 ASAH1 T REC no hist CC + CT pravastatin72 hCV2442143 rs12544854 ASAH1 T REC no hist CC + CT placebo 68hCV2442143 rs12544854 ASAH1 T DOM hist TT + CT pravastatin 88 hCV2442143rs12544854 ASAH1 T DOM hist TT + CT placebo 82 hCV27830265 rs12762303ALOX5 G DOM no hist GG + AG pravastatin 25 hCV27830265 rs12762303 ALOX5G DOM no hist GG + AG placebo 16 hCV2169762 rs1804689  HPS1 T GEN nohist TT pravastatin 10 hCV2169762 rs1804689  HPS1 T GEN no hist TTplacebo 9 hCV2169762 rs1804689  HPS1 T GEN no hist GT pravastatin 47hCV2169762 rs1804689  HPS1 T GEN no hist GT placebo 38 hCV2169762rs1804689  HPS1 T GEN no hist GG pravastatin 30 hCV2169762 rs1804689 HPS1 T GEN no hist GG placebo 47 hCV2169762 rs1804689  HPS1 T DOM nohist TT + GT pravastatin 57 hCV2169762 rs1804689  HPS1 T DOM no histTT + GT placebo 47 hCV2169762 rs1804689  HPS1 T GEN hist TT pravastatin5 hCV2169762 rs1804689  HPS1 T GEN hist TT placebo 12 hCV2169762rs1804689  HPS1 T GEN hist GT pravastatin 47 hCV2169762 rs1804689  HPS1T GEN hist GT placebo 46 hCV2169762 rs1804689  HPS1 T GEN hist GGpravastatin 62 hCV2169762 rs1804689  HPS1 T GEN hist GG placebo 56hCV2169762 rs1804689  HPS1 T REC hist GG + GT pravastatin 109 hCV2169762rs1804689  HPS1 T REC hist GG + GT placebo 102 hCV1348610 rs3739636 C9orf46 A GEN hist AA pravastatin 24 hCV1348610 rs3739636  C9orf46 A GENhist AA placebo 19 hCV1348610 rs3739636  C9orf46 A GEN hist AGpravastatin 47 hCV1348610 rs3739636  C9orf46 A GEN hist AG placebo 61hCV1348610 rs3739636  C9orf46 A GEN hist GG pravastatin 43 hCV1348610rs3739636  C9orf46 A GEN hist GG placebo 35 hCV1348610 rs3739636 C9orf46 A DOM hist AA + AG pravastatin 71 hCV1348610 rs3739636  C9orf46A DOM hist AA + AG placebo 80 hCV27511436 rs3750145  FZD1 T GEN no histCC pravastatin 1 hCV27511436 rs3750145  FZD1 T GEN no hist CC placebo 3hCV27511436 rs3750145  FZD1 T GEN no hist CT pravastatin 26 hCV27511436rs3750145  FZD1 T GEN no hist CT placebo 16 hCV27511436 rs3750145  FZD1T GEN no hist TT pravastatin 60 hCV27511436 rs3750145  FZD1 T GEN nohist TT placebo 75 hCV27511436 rs3750145  FZD1 T DOM no hist CC + CTpravastatin 27 hCV27511436 rs3750145  FZD1 T DOM no hist CC + CT placebo19 no TOTAL_ LOWER_ UPPER_ P_INT_ hCV # event RESP HR_RESP RESP RESPP_RESP RESP hCV2091644 258 271 0.635895 0.31841 1.26996 0.1995630.1798335 hCV2091644 265 286 0.1798335 hCV2091644 736 773 0.8503560.5516 1.31092 0.462931 0.1798335 hCV2091644 768 814 0.1798335hCV2091644 492 528 1.358113 0.82457 2.2369 0.22925 0.1798335 hCV2091644510 537 0.1798335 hCV2091644 994 1044 0.786037 0.54496 1.13377 0.1976770.0837336 hCV2091644 1033 1100 0.0837336 hCV29539757 96 103 0.4114870.16926 1.00034 0.050088 0.1548877 hCV29539757 92 108 0.1548877hCV29539757 493 537 0.994615 0.6549 1.51055 0.979793 0.1548877hCV29539757 481 525 0.1548877 hCV29539757 594 656 1.015618 0.707621.45767 0.93301 0.1548877 hCV29539757 559 615 0.1548877 hCV29539757 10871193 1.008802 0.76761 1.32578 0.949874 0.0530448 hCV29539757 1040 11400.0530448 hCV26505812 638 689 1.081641 0.7293 1.60421 0.696354 0.0696553hCV26505812 653 701 0.0696553 hCV26505812 1349 1443 0.776862 0.593351.01713 0.066291 0.0696553 hCV26505812 1334 1455 0.0696553 hCV26505812674 730 1.330498 0.88923 1.99075 0.164856 0.0696553 hCV26505812 680 7210.0696553 hCV26505812 1987 2132 0.863809 0.69193 1.07838 0.1958990.0630809 hCV26505812 1987 2156 0.0630809 hCV26505812 333 357 1.0681050.6028 1.89259 0.821407 0.0828923 hCV26505812 341 364 0.0828923hCV26505812 754 789 0.697717 0.45454 1.071 0.099711 0.0828923hCV26505812 774 826 0.0828923 hCV26505812 395 423 1.570465 0.876952.81243 0.128942 0.0828923 hCV26505812 424 443 0.0828923 hCV265058121087 1146 0.813189 0.57817 1.14374 0.234739 0.0573322 hCV26505812 11151190 0.0573322 hCV2442143 1146 1218 1.087339 0.78059 1.51463 0.6204890.1385034 hCV2442143 1175 1243 0.1385034 hCV2442143 865 953 1.0433070.77225 1.4095 0.78239 0.1787787 hCV2442143 850 932 0.1787787hCV27830265 474 499 1.479294 0.78982 2.77065 0.22133 0.1332561hCV27830265 445 461 0.1332561 hCV2169762 127 137 1.27501 0.51771 3.140080.597269 0.102835  hCV2169762 145 154 0.102835  hCV2169762 604 6511.268286 0.82701 1.94501 0.27599 0.102835  hCV2169762 632 670 0.102835 hCV2169762 753 783 0.65902 0.41685 1.04187 0.074354 0.102835  hCV2169762763 810 0.102835  hCV2169762 731 788 1.265576 0.86016 1.86208 0.2319320.033   hCV2169762 777 824 0.033   hCV2169762 119 124 0.336546 0.118470.95606 0.040922 0.1254774 hCV2169762 99 111 0.1254774 hCV2169762 511558 0.94255 0.62771 1.4153 0.775439 0.1254774 hCV2169762 480 5260.1254774 hCV2169762 552 614 1.104484 0.76954 1.58521 0.589855 0.1254774hCV2169762 555 611 0.1254774 hCV2169762 1063 1172 1.02768 0.7845 1.346240.842894 0.0507564 hCV2169762 1035 1137 0.0507564 hCV1348610 226 2500.986092 0.54 1.80071 0.963642 0.1842815 hCV1348610 186 205 0.1842815hCV1348610 566 613 0.740596 0.50624 1.08345 0.121846 0.1842815hCV1348610 545 606 0.1842815 hCV1348610 378 421 1.276897 0.81723 1.995110.283036 0.1842815 hCV1348610 392 427 0.1842815 hCV1348610 792 8630.806434 0.58581 1.11014 0.187096 0.1002517 hCV1348610 731 811 0.1002517hCV27511436 42 43 0.349207 0.03631 3.35808 0.362284 0.1652143hCV27511436 43 46 0.1652143 hCV27511436 407 433 1.575251 0.84504 2.936450.152693 0.1652143 hCV27511436 398 414 0.1652143 hCV27511436 1035 10950.85237 0.60701 1.19691 0.356417 0.1652143 hCV27511436 1099 11740.1652143 hCV27511436 449 476 1.387947 0.77175 2.49613 0.2736260.1600111 hCV27511436 441 460 0.1600111

TABLE 33 gene/ chrom GENO hCV # rs # symbol ENDPT MODE STRATA ADJUSTTYPE hCV1348610 rs3739636 C9orf46 ATHERO GEN WHITE AGEBL GEND01 AGhCV15857769 rs2924914 ATHERO GEN WHITE AGEBL GEND01 TT hCV15857769rs2924914 ATHERO REC WHITE AGEBL GEND01 TT hCV15857769 rs2924914 ATHEROADD WHITE AGEBL GEND01 T hCV15857769 rs2924914 ATHERO GEN WHITE AGEBLGEND01 TT BMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV15857769 rs2924914ATHERO REC WHITE AGEBL GEND01 TT BMI PRESSM DIABADA HTN LDLADJBL HDL44BLhCV15857769 rs2924914 ISCHEM GEN WHITE AGEBL GEND01 TT hCV15857769rs2924914 ISCHEM REC WHITE AGEBL GEND01 TT hCV15857769 rs2924914 ISCHEMADD WHITE AGEBL GEND01 T hCV15857769 rs2924914 ISCHEM GEN WHITE AGEBLGEND01 TT BMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV15857769 rs2924914ISCHEM ADD WHITE AGEBL GEND01 T BMI PRESSM DIABADA HTN LDLADJBL HDL44BLhCV15857769 rs2924914 STROKE GEN WHITE AGEBL GEND01 TT hCV16336rs362277  HD STROKE ADD WHITE AGEBL GEND01 C hCV30308202 rs9482985 LAMA2ISCHEM REC WHITE AGEBL GEND01 GG hCV30308202 rs9482985 LAMA2 ISCHEM RECWHITE AGEBL GEND01 GG BMI PRESSM DIABADA HTN LDLADJBL HDL44BL 95% 95% P-Lower Upper VALUE CL for CL for 2- 2DF P- hCV # EVENTS TOTAL HR HR HRsided) VALUE hCV1348610 147 1809 1.28 0.97 1.70 0.087 0.232 hCV1585776931 310 1.52 1.03 2.26 0.036 0.111 hCV15857769 31 310 1.47 1.01 2.130.046 . hCV15857769 . . 1.19 0.99 1.43 0.066 . hCV15857769 30 300 1.460.98 2.17 0.067 0.186 hCV15857769 30 300 1.4 0.96 2.06 0.083 .hCV15857769 41 310 1.42 1.01 1.99 0.044 0.127 hCV15857769 41 310 1.360.98 1.88 0.064 . hCV15857769 . . 1.16 0.99 1.35 0.060 . hCV15857769 40300 1.36 0.97 1.93 0.078 0.202 hCV15857769 . . 1.14 0.98 1.34 0.093 .hCV15857769 48 310 1.32 0.96 1.80 0.084 0.220 hCV16336 . . 1.2 0.97 1.490.093 . hCV30308202 280 2509 1.21 0.98 1.50 0.080 . hCV30308202 275 24581.21 0.98 1.51 0.080 .

TABLE 34 gene/ chrom GENO hCV # rs # symbol ENDPT MODE STRATA ADJUSTTYPE hCV1348610 rs3739636  C9orf46 ATHERO GEN BLACK AGEBL GEND01 AA BMIPRESSM DIABADA HTN LDLADJBL HDL44BL hCV1348610 rs3739636  C9orf46 ATHEROADD BLACK AGEBL GEND01 A BMI PRESSM DIABADA HTN LDLADJBL HDL44BLhCV1348610 rs3739636  C9orf46 ISCHEM GEN BLACK AGEBL GEND01 AA BMIPRESSM DIABADA HTN LDLADJBL HDL44BL hCV1348610 rs3739636  C9orf46 ISCHEMADD BLACK AGEBL GEND01 A BMI PRESSM DIABADA HTN LDLADJBL HDL44BLhCV1348610 rs3739636  C9orf46 STROKE GEN BLACK AGEBL GEND01 AA BMIPRESSM DIABADA HTN LDLADJBL HDL44BL hCV1348610 rs3739636  C9orf46 STROKEREC BLACK AGEBL GEND01 AA BMI PRESSM DIABADA HTN LDLADJBL HDL44BLhCV1348610 rs3739636  C9orf46 STROKE ADD BLACK AGEBL GEND01 A BMI PRESSMDIABADA HTN LDLADJBL HDL44BL hCV1619596 rs1048621  SDCBP2 ISCHEM GENBLACK AGEBL GEND01 AA hCV1619596 rs1048621  SDCBP2 ISCHEM REC BLACKAGEBL GEND01 AA hCV1619596 rs1048621  SDCBP2 ISCHEM GEN BLACK AGEBLGEND01 AA BMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV1619596 rs1048621 SDCBP2 ISCHEM REC BLACK AGEBL GEND01 AA BMI PRESSM DIABADA HTN LDLADJBLHDL44BL hCV1619596 rs1048621  SDCBP2 STROKE GEN BLACK AGEBL GEND01 AAhCV1619596 rs1048621  SDCBP2 STROKE REC BLACK AGEBL GEND01 AA hCV1619596rs1048621  SDCBP2 STROKE GEN BLACK AGEBL GEND01 AA BMI PRESSM DIABADAHTN LDLADJBL HDL44BL hCV1619596 rs1048621  SDCBP2 STROKE REC BLACK AGEBLGEND01 AA BMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV16336 rs362277  HDISCHEM GEN BLACK AGEBL GEND01 CT hCV16336 rs362277  HD ISCHEM GEN BLACKAGEBL GEND01 CT BMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV1723718rs12481805 UMODL1 ATHERO GEN BLACK AGEBL GEND01 AA hCV1723718 rs12481805UMODL1 ATHERO REC BLACK AGEBL GEND01 AA hCV1723718 rs12481805 UMODL1ATHERO GEN BLACK AGEBL GEND01 AA BMI PRESSM DIABADA HTN LDLADJBL HDL44BLhCV1723718 rs12481805 UMODL1 ATHERO REC BLACK AGEBL GEND01 AA BMI PRESSMDIABADA HTN LDLADJBL HDL44BL hCV1723718 rs12481805 UMODL1 ISCHEM GENBLACK AGEBL GEND01 AA hCV1723718 rs12481805 UMODL1 ISCHEM REC BLACKAGEBL GEND01 AA hCV1723718 rs12481805 UMODL1 ISCHEM GEN BLACK AGEBLGEND01 AA BMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV1723718 rs12481805UMODL1 ISCHEM REC BLACK AGEBL GEND01 AA BMI PRESSM DIABADA HTN LDLADJBLHDL44BL hCV25596936 rs6967117  EPHA1 STROKE GEN BLACK AGEBL GEND01 TTBMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV25596936 rs6967117  EPHA1STROKE REC BLACK AGEBL GEND01 TT BMI PRESSM DIABADA HTN LDLADJBL HDL44BLhCV27077072 rs8060368  ATHERO REC BLACK AGEBL GEND01 CC hCV27077072rs8060368  ATHERO ADD BLACK AGEBL GEND01 C hCV27077072 rs8060368  ATHEROADD BLACK AGEBL GEND01 C BMI PRESSM DIABADA HTN LDLADJBL HDL44BLhCV27077072 rs8060368  ISCHEM ADD BLACK AGEBL GEND01 C hCV8754449rs781226  TESK2 ATHERO GEN BLACK AGEBL GEND01 CT BMI PRESSM DIABADA HTNLDLADJBL HDL44BL hCV8754449 rs781226  TESK2 ISCHEM GEN BLACK AGEBLGEND01 CT BMI PRESSM DIABADA HTN LDLADJBL HDL44BL 95% 95% P- Lower UpperVALUE CL for CL for (2- 2DF P- hCV # EVENTS TOTAL HR HR HR sided) VALUEhCV1348610 17 151 2.03 0.93 4.40 0.074 0.203 hCV1348610 . . 1.41 0.972.06 0.073 . hCV1348610 20 151 1.83 0.91 3.67 0.089 0.214 hCV1348610 . .1.36 0.96 1.93 0.085 . hCV1348610 25 151 1.75 0.94 3.23 0.076 0.173hCV1348610 25 151 1.56 0.96 2.54 0.075 . hCV1348610 . . 1.33 0.98 1.820.072 . hCV1619596 6 22 2.36 1.00 5.60 0.051 0.150 hCV1619596 6 22 2.280.98 5.32 0.055 . hCV1619596 5 20 2.66 1.02 6.90 0.045 0.133 hCV16195965 20 2.54 1.00 6.46 0.050 . hCV1619596 7 22 2.15 0.97 4.75 0.059 0.165hCV1619596 7 22 2.12 0.97 4.61 0.059 . hCV1619596 6 20 2.24 0.95 5.310.067 0.185 hCV1619596 6 20 2.2 0.95 5.14 0.068 . hCV16336 43 326 1.680.92 3.07 0.094 0.083 hCV16336 41 309 1.95 1.02 3.71 0.043 0.033hCV1723718 3 8 3.95 1.21 12.91 0.023 0.046 hCV1723718 3 8 4.15 1.2813.49 0.018 . hCV1723718 3 8 3.4 1.00 11.56 0.051 0.085 hCV1723718 3 83.61 1.07 12.22 0.039 . hCV1723718 3 8 3.26 1.01 10.59 0.049 0.073hCV1723718 3 8 3.46 1.07 11.17 0.038 . hCV1723718 3 8 3.08 0.92 10.320.068 0.096 hCV1723718 3 8 3.29 0.99 10.95 0.052 . hCV25596936 1 4 70.80 61.25 0.079 0.170 hCV25596936 1 4 6.66 0.77 58.06 0.086 .hCV27077072 48 444 1.78 0.96 3.29 0.066 . hCV27077072 . . 1.82 1.03 3.240.041 . hCV27077072 . . 1.64 0.91 2.95 0.097 . hCV27077072 . . 1.56 0.942.59 0.087 . hCV8754449 35 297 1.86 0.99 3.46 0.052 0.081 hCV8754449 39297 1.8 1.01 3.24 0.048 0.085

TABLE 35 gene/ chrom GENO- hCV # rs # symbol ENDPT MODE STRATA ADJUSTTYPE hCV11425801 rs3805953  PEX6 ISCHEM GEN WHITE AGEBL GEND01 CT BMIPRESSM DIABADA HTN LDLADJBL HDL44BL hCV11425801 rs3805953  PEX6 STROKEGEN WHITE AGEBL GEND01 CT BMI PRESSM DIABADA HTN LDLADJBL HDL44BLhCV1348610 rs3739636  C9orf46 ATHERO DOM WHITE AGEBL GEND01 AG + AAhCV1348610 rs3739636  C9orf46 ATHERO GEN WHITE AGEBL GEND01 AG BMIPRESSM DIABADA HTN LDLADJBL HDL44BL hCV1348610 rs3739636  C9orf46 ATHERODOM WHITE AGEBL GEND01 AG + AA BMI PRESSM DIABADA HTN LDLADJBL HDL44BLhCV15857769 rs2924914  ATHERO ADD WHITE AGEBL GEND01 T BMI PRESSMDIABADA HTN LDLADJBL HDL44BL hCV15857769 rs2924914  ISCHEM DOM WHITEAGEBL GEND01 TC + TT hCV15857769 rs2924914  ISCHEM REC WHITE AGEBLGEND01 TT BMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV15857769 rs2924914 STROKE REC WHITE AGEBL GEND01 TT hCV15857769 rs2924914  STROKE ADD WHITEAGEBL GEND01 T hCV15857769 rs2924914  STROKE GEN WHITE AGEBL GEND01 TTBMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV15857769 rs2924914  STROKEREC WHITE AGEBL GEND01 TT BMI PRESSM DIABADA HTN LDLADJBL HDL44BLhCV15857769 rs2924914  STROKE ADD WHITE AGEBL GEND01 T BMI PRESSMDIABADA HTN LDLADJBL HDL44BL hCV16158671 rs2200733  STROKE GEN WHITEAGEBL GEND01 TT hCV16158671 rs2200733  STROKE REC WHITE AGEBL GEND01 TThCV16158671 rs2200733  STROKE GEN WHITE AGEBL GEND01 TT BMI PRESSMDIABADA HTN LDLADJBL HDL44BL hCV16158671 rs2200733  STROKE REC WHITEAGEBL GEND01 TT BMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV16336rs362277  HD STROKE GEN WHITE AGEBL GEND01 CC hCV16336 rs362277  HDSTROKE DOM WHITE AGEBL GEND01 CT + CC hCV16336 rs362277  HD STROKE RECWHITE AGEBL GEND01 CC hCV16336 rs362277  HD STROKE ADD WHITE AGEBLGEND01 C BMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV29401764 rs7793552 LOC646588 ISCHEM REC WHITE AGEBL GEND01 CC hCV30308202 rs9482985  LAMA2ISCHEM ADD WHITE AGEBL GEND01 G hCV30308202 rs9482985  LAMA2 ISCHEM ADDWHITE AGEBL GEND01 G BMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV30308202rs9482985  LAMA2 STROKE REC WHITE AGEBL GEND01 GG hCV32160712 rs11079160ATHERO GEN WHITE AGEBL GEND01 TT hCV32160712 rs11079160 ATHERO REC WHITEAGEBL GEND01 TT hCV32160712 rs11079160 ATHERO GEN WHITE AGEBL GEND01 TTBMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV32160712 rs11079160 ATHEROREC WHITE AGEBL GEND01 TT BMI PRESSM DIABADA HTN LDLADJBL HDL44BL 95%95% P- Lower Upper VALUE CL for CL for (2- 2DF P- hCV # EVENTS TOTAL HRHR HR sided) VALUE hCV11425801 206 1814 1.17 0.928 1.48 0.1834 0.1314hCV11425801 254 1814 1.15 0.933 1.418 0.1894 0.1374 hCV1348610 205 25561.25 0.953 1.631 0.108 . hCV1348610 143 1763 1.25 0.938 1.658 0.12860.3147 hCV1348610 201 2499 1.22 0.933 1.605 0.1444 . hCV15857769 . .1.17 0.969 1.403 0.1033 . hCV15857769 187 1704 1.16 0.942 1.422 0.165 .hCV15857769 40 300 1.31 0.942 1.821 0.1092 . hCV15857769 48 310 1.280.947 1.723 0.1093 . hCV15857769 . . 1.12 0.974 1.288 0.1112 .hCV15857769 47 300 1.29 0.939 1.766 0.1172 0.2918 hCV15857769 47 3001.26 0.928 1.702 0.1394 . hCV15857769 . . 1.11 0.96 1.274 0.1632 .hCV16158671 16 90 1.41 0.853 2.323 0.1811 0.4076 hCV16158671 16 90 1.40.85 2.306 0.1856 . hCV16158671 16 88 1.48 0.895 2.443 0.1272 0.3047hCV16336 408 3030 2.2 0.707 6.862 0.1734 0.2057 hCV16336 495 3764 2.140.689 6.677 0.188 . hCV16336 408 3030 1.19 0.944 1.49 0.1428 . hCV16336. . 1.16 0.937 1.44 0.1709 . hCV29401764 199 1792 1.15 0.941 1.3950.1757 . hCV30308202 . . 1.14 0.946 1.368 0.1694 . hCV30308202 . . 1.140.949 1.374 0.1586 . hCV30308202 342 2509 1.14 0.942 1.376 0.1802 .hCV32160712 13 119 1.47 0.835 2.572 0.183 0.3099 hCV32160712 13 119 1.50.858 2.617 0.1551 . hCV32160712 13 117 1.49 0.851 2.626 0.1621 0.2277hCV32160712 13 117 1.54 0.883 2.698 0.1277 .

TABLE 36 gene/ chrom GENO hCV # rs # symbol ENDPT MODE STRATA ADJUSTTYPE hCV11425801 rs3805953  PEX6 ISCHEM GEN BLACK AGEBL GEND01 CThCV11425801 rs3805953  PEX6 ISCHEM GEN BLACK AGEBL GEND01 CT BMI PRESSMDIABADA HTN LDLADJBL HDL44BL hCV11425801 rs3805953  PEX6 STROKE GENBLACK AGEBL GEND01 CT hCV11425801 rs3805953  PEX6 STROKE GEN BLACK AGEBLGEND01 CT BMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV11425842 rs10948059GNMT ATHERO GEN BLACK AGEBL GEND01 CC BMI PRESSM DIABADA HTN LDLADJBLHDL44BL hCV11425842 rs10948059 GNMT ATHERO REC BLACK AGEBL GEND01 CC BMIPRESSM DIABADA HTN LDLADJBL HDL44BL hCV11425842 rs10948059 GNMT ATHEROADD BLACK AGEBL GEND01 C BMI PRESSM DIABADA HTN LDLADJBL HDL44BLhCV11425842 rs10948059 GNMT STROKE GEN BLACK AGEBL GEND01 CC BMI PRESSMDIABADA HTN LDLADJBL HDL44BL hCV11425842 rs10948059 GNMT STROKE ADDBLACK AGEBL GEND01 C BMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV1348610rs3739636  C9orf46 ATHERO GEN BLACK AGEBL GEND01 AA hCV1348610rs3739636  C9orf46 ATHERO DOM BLACK AGEBL GEND01 AG + AA BMI PRESSMDIABADA HTN LDLADJBL HDL44BL hCV1348610 rs3739636  C9orf46 ATHERO RECBLACK AGEBL GEND01 AA BMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV1348610rs3739636  C9orf46 ISCHEM REC BLACK AGEBL GEND01 AA BMI PRESSM DIABADAHTN LDLADJBL HDL44BL hCV1619596 rs1048621  SDCBP2 ISCHEM ADD BLACK AGEBLGEND01 A hCV1619596 rs1048621  SDCBP2 ISCHEM ADD BLACK AGEBL GEND01 ABMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV16336 rs362277  HD ATHERO GENBLACK AGEBL GEND01 CT BMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV16336rs362277  HD ISCHEM DOM BLACK AGEBL GEND01 CT + CC BMI PRESSM DIABADAHTN LDLADJBL HDL44BL hCV16336 rs362277  HD STROKE GEN BLACK AGEBL GEND01CT BMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV1723718 rs12481805 UMODL1STROKE GEN BLACK AGEBL GEND01 AA hCV1723718 rs12481805 UMODL1 STROKE RECBLACK AGEBL GEND01 AA hCV1723718 rs12481805 UMODL1 STROKE GEN BLACKAGEBL GEND01 AA BMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV1723718rs12481805 UMODL1 STROKE REC BLACK AGEBL GEND01 AA BMI PRESSM DIABADAHTN LDLADJBL HDL44BL hCV25596936 rs6967117  EPHA1 STROKE GEN BLACK AGEBLGEND01 TT hCV25596936 rs6967117  EPHA1 STROKE REC BLACK AGEBL GEND01 TThCV27077072 rs8060368  ATHERO REC BLACK AGEBL GEND01 CC BMI PRESSMDIABADA HTN LDLADJBL HDL44BL hCV27077072 rs8060368  ISCHEM REC BLACKAGEBL GEND01 CC hCV27077072 rs8060368  ISCHEM ADD BLACK AGEBL GEND01 CBMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV29401764 rs7793552  LOC646588STROKE GEN BLACK AGEBL GEND01 CC hCV29401764 rs7793552  LOC646588 STROKEREC BLACK AGEBL GEND01 CC hCV29401764 rs7793552  LOC646588 STROKE GENBLACK AGEBL GEND01 CC BMI PRESSM DIABADA HTN LDLADJBL HDL44BLhCV29401764 rs7793552  LOC646588 STROKE REC BLACK AGEBL GEND01 CC BMIPRESSM DIABADA HTN LDLADJBL HDL44BL hCV8754449 rs781226  TESK2 ATHEROGEN BLACK AGEBL GEND01 CT hCV8754449 rs781226  TESK2 ATHERO DOM BLACKAGEBL GEND01 CT + CC BMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV8754449rs781226  TESK2 ISCHEM DOM BLACK AGEBL GEND01 CT + CC BMI PRESSM DIABADAHTN LDLADJBL HDL44BL hCV8754449 rs781226  TESK2 STROKE GEN BLACK AGEBLGEND01 CT BMI PRESSM DIABADA HTN LDLADJBL HDL44BL hCV8942032 rs1264352 DDR1 STROKE GEN BLACK AGEBL GEND01 CG hCV8942032 rs1264352  DDR1 STROKEGEN BLACK AGEBL GEND01 CG BMI PRESSM DIABADA HTN LDLADJBL HDL44BL 95%95% P- Lower Upper VALUE CL for CL for (2- 2DF P- hCV # EVENTS TOTAL HRHR HR sided) VALUE hCV11425801 25 184 1.4 0.853 2.286 0.1849 0.4151hCV11425801 24 177 1.47 0.882 2.446 0.1399 0.3364 hCV11425801 30 1841.35 0.865 2.119 0.1854 0.1546 hCV11425801 29 177 1.39 0.88 2.209 0.15740.145 hCV11425842 19 158 1.63 0.789 3.384 0.1864 0.3447 hCV11425842 19158 1.5 0.857 2.628 0.1557 . hCV11425842 . . 1.29 0.894 1.872 0.1716 .hCV11425842 25 158 1.51 0.822 2.78 0.1837 0.4087 hCV11425842 . . 1.230.908 1.664 0.181 . hCV1348610 17 157 1.64 0.769 3.515 0.1995 0.4376hCV1348610 39 427 1.72 0.865 3.421 0.1223 . hCV1348610 17 151 1.54 0.8552.786 0.1497 . hCV1348610 20 151 1.57 0.91 2.713 0.1048 . hCV1619596 . .1.33 0.902 1.954 0.1502 . hCV1619596 . . 1.37 0.904 2.084 0.1373 .hCV16336 34 309 1.61 0.832 3.118 0.1574 0.1458 hCV16336 53 469 1.6 0.8533 0.1434 . hCV16336 48 309 1.44 0.846 2.456 0.1788 0.1231 hCV1723718 3 82.45 0.763 7.88 0.1323 0.1146 hCV1723718 3 8 2.62 0.816 8.39 0.1057 .hCV1723718 3 8 2.28 0.692 7.493 0.1755 0.1501 hCV1723718 3 8 2.44 0.7468.015 0.1401 . hCV25596936 1 4 4.13 0.551 31.03 0.1676 0.3443hCV25596936 1 4 4.04 0.539 30.26 0.1741 . hCV27077072 44 423 1.59 0.8522.96 0.1453 . hCV27077072 53 444 1.48 0.859 2.566 0.1567 . hCV27077072 .. 1.51 0.891 2.567 0.125 . hCV29401764 13 61 1.62 0.855 3.084 0.13820.3119 hCV29401764 13 61 1.58 0.873 2.848 0.1313 . hCV29401764 12 571.62 0.836 3.15 0.1529 0.3156 hCV29401764 12 57 1.61 0.87 2.981 0.1291 .hCV8754449 36 310 1.49 0.836 2.657 0.1758 0.1929 hCV8754449 43 414 1.610.879 2.966 0.1228 . hCV8754449 49 414 1.59 0.899 2.806 0.1107 .hCV8754449 46 297 1.39 0.847 2.289 0.192 0.1777 hCV8942032 38 244 1.340.867 2.058 0.1894 0.1396 hCV8942032 36 229 1.43 0.915 2.25 0.11550.0872

TABLE 37 hCV # (C9p21 rs # (C9p21 GENO- SNP) SNP) ADJUST MODE TYPESTATIN EVENTS hCV26505812 rs10757274 unadjusted GEN AA Pravastatin 17hCV26505812 rs10757274 unadjusted GEN AA Placebo 17 hCV26505812rs10757274 unadjusted GEN AG Pravastatin 27 hCV26505812 rs10757274unadjusted GEN AG Placebo 48 hCV26505812 rs10757274 unadjusted GEN GGPravastatin 23 hCV26505812 rs10757274 unadjusted GEN GG Placebo 25hCV26505812 rs10757274 unadjusted DOM AG + AA Pravastatin 44 hCV26505812rs10757274 unadjusted DOM AG + AA Placebo 65 hCV26505812 rs10757274unadjusted REC AG + GG Pravastatin 50 hCV26505812 rs10757274 unadjustedREC AG + GG Placebo 73 hCV26505812 rs10757274 AGE MALE CURRSMK GEN AAPravastatin 18 HYPERTEN_1 DIABETES_1 BMI BASE_LDL BASE_HD1 hCV26505812rs10757274 AGE_MALE CURRSMK GEN AA Placebo 17 HYPERTEN_1 DIABETES_1 BMIBASE_EDL BASE_HD1 hCV26505812 rs10757274 AGE_MALE CURRSMK GEN GAPravastatin 29 HYPERTEN_1 DIABETES_1 BMI BASE_EDL BASE_HD1 hCV26505812rs10757274 AGE_MALE CURRSMK GEN GA Placebo 50 HYPERTEN_1 DIABETES_1 BMIBASE_EDL BASE_HD1 hCV26505812 rs10757274 AGE_MALE CURRSMK GEN GGPravastatin 25 HYPERTEN_1 DIABETES_1 BMI BASE_EDL BASE_HD1 hCV26505812rs10757274 AGE MALE CURRSMK GEN GG Placebo 26 HYPERTEN_1 DIABETES_1 BMIBASE_EDL BASE_HD1 hCV26505812 rs10757274 AGE MALE CURRSMK REC GA + AAPravastatin 47 HYPERTEN_1 DIABETES_1 BMI BASE_EDL BASE_HD1 hCV26505812rs10757274 AGE MALE CURRSMK REC GA + AA Placebo 67 HYPERTEN_1 DIABETES_1BMI BASE_EDL BASE_HD1 hCV26505812 rs10757274 AGE MALE CURRSMK DOM GA +GG Pravastatin 54 HYPERTEN_1 DIABETES_1 BMI BASE_EDL BASE_HD1hCV26505812 rs10757274 AGE MALE CURRSMK DOM GA + GG Placebo 76HYPERTEN_1 DIABETES_1 BMI BASE_EDL BASE_HD1 95% 95% Lower UpperConfidence Confidence Limit for Limit for hCV # (C9p21 Hazard Hazard P-PVAL_IN SNP) TOTAL HR Ratio Ratio VALUE TX hCV26505812 315 0.85 0.4331.667 0.6359 0.44429 hCV26505812 262 ref . . . 0.44429 hCV26505812 6660.58 0.361 0.927 0.0229 0.44429 hCV26505812 689 ref . . . 0.44429hCV26505812 414 0.91 0.515 1.599 0.7377 0.44429 hCV26505812 412 ref . .. 0.44429 hCV26505812 981 0.65 0.446 0.96  0.03  0.34883 hCV26505812 951ref . . . 0.34883 hCV26505812 1080 0.69 0.484 0.994 0.0463 0.65126hCV26505812 1101 ref . . . 0.65126 hCV26505812 328 0.92 0.469 1.8020.8064 0.43653 hCV26505812 272 ref . . . 0.43653 hCV26505812 690 0.610.384 0.963 0.0339 0.43653 hCV26505812 727 ref . . . 0.43653 hCV26505812441 1 0.574 1.732 0.9924 0.43653 hCV26505812 425 ref . . . 0.43653hCV26505812 1018 0.69 0.476 1.005 0.0533 0.3725  hCV26505812 999 ref . .. 0.3725  hCV26505812 1131 0.73 0.512 1.03  0.0728 0.60059 hCV265058121152 ref . . . 0.60059

TABLE 38 for chromosome 9p21 SNP (rs10757274/hCV26505812): HR_ LOWER_UPPER_ P_ Risk GENO_ EVENTS_ no TOTAL_ RESP_ RESP_ RESP_ RESP_ ENDPTAllele MODE STRATA RESP STATIN RESP event RESP unadj unadj unadj unadjstroke G GEN ALL GG pravastatin 51 638 689 1.082 0.729 1.604 0.696stroke G GEN ALL GG placebo 48 653 701 stroke G GEN ALL AG pravastatin94 1349 1443 0.777 0.593 1.017 0.066 stroke G GEN ALL AG placebo 1211334 1455 stroke G GEN ALL AA pravastatin 56 674 730 1.330 0.889 1.9910.165 stroke G GEN ALL AA placebo 41 680 721 stroke G DOM ALL GG + AGpravastatin 145 1987 2132 0.864 0.692 1.078 0.196 stroke G DOM ALL GG +AG placebo 169 1987 2156 stroke G REC ALL AA + AG pravastatin 150 20232173 0.919 0.736 1.147 0.455 stroke G REC ALL AA + AG placebo 162 20142176 stroke G GEN no hist GG pravastatin 24 333 357 1.068 0.603 1.8930.821 stroke G GEN no hist GG placebo 23 341 364 stroke G GEN no hist AGpravastatin 35 754 789 0.698 0.455 1.071 0.100 stroke G GEN no hist AGplacebo 52 774 826 stroke G GEN no hist AA pravastatin 28 395 423 1.5700.877 2.812 0.129 stroke G GEN no hist AA placebo 19 424 443 stroke GDOM no hist GG + AG pravastatin 59 1087 1146 0.813 0.578 1.144 0.235stroke G DOM no hist GG + AG placebo 75 1115 1190 stroke G REC no histAA + AG pravastatin 63 1149 1212 0.927 0.660 1.302 0.662 stroke G REC nohist AA + AG placebo 71 1198 1269 stroke G GEN hist GG pravastatin 27305 332 1.098 0.637 1.892 0.736 stroke G GEN hist GG placebo 25 312 337stroke G GEN hist AG pravastatin 59 595 654 0.816 0.576 1.155 0.251stroke G GEN hist AG placebo 69 560 629 stroke G GEN hist AA pravastatin28 279 307 1.093 0.625 1.911 0.755 stroke G GEN hist AA placebo 22 256278 stroke G DOM hist GG + AG pravastatin 86 900 986 0.892 0.666 1.1950.444 stroke G DOM hist GG + AG placebo 94 872 966 stroke G REC histAA + AG pravastatin 87 874 961 0.885 0.660 1.187 0.415 stroke G REC histAA + AG placebo 91 816 907 P_INT_ P_ P_INT_ GENO_ EVENTS_ TOTAL_ HR_LOWER_ UPPER_ P_ Risk RESP_ RESP_ RESP_ PLA- PLA- PLA- PLA- PLA- PLA-PLA- ENDPT Allele MODE unadj adj adj CEBO CEBO CEBO CEBO CEBO CEBO CEBOstroke G GEN 0.070 0.602 0.050 GG 48 701 1.20631 0.79513 1.8301 0.37779stroke G GEN 0.070 0.050 stroke G GEN 0.070 0.053 0.050 AG 121 14551.46444 1.02767 2.0868 0.03477 stroke G GEN 0.070 0.050 stroke G GEN0.070 0.158 0.050 AA 41 721 ref 0 0 0     stroke G GEN 0.070 0.050stroke G DOM 0.063 0.175 0.055 GG + AG 169 2156 1.38115 0.98188 1.94280.06361 stroke G DOM 0.063 0.055 stroke G REC 0.472 0.432 0.398 AA + AGstroke G REC 0.472 0.398 stroke G GEN 0.083 0.824 0.065 GG 23 3641.50713 0.82085 2.7672 0.18578 stroke G GEN 0.083 0.065 stroke G GEN0.083 0.077 0.065 AG 52 826 1.48278 0.87679 2.5076 0.1417  stroke G GEN0.083 0.065 stroke G GEN 0.083 0.108 0.065 AA 19 443 ref 0 0 0    stroke G GEN 0.083 0.065 stroke G DOM 0.057 0.191 0.049 GG + AG 75 11901.489 0.90012 2.4632 0.12109 stroke G DOM 0.057 0.049 stroke G REC 0.6690.636 0.624 AA + AG stroke G REC 0.669 0.624 stroke G GEN 0.535 0.6500.576 GG 25 337 0.91337 0.51499 1.6199 0.75659 stroke G GEN 0.535 0.576stroke G GEN 0.535 0.323 0.576 AG 69 629 1.37223 0.84919 2.2174 0.19624stroke G GEN 0.535 0.576 stroke G GEN 0.535 0.978 0.576 AA 22 278 ref 00 0     stroke G GEN 0.535 0.576 stroke G DOM 0.508 0.552 0.576 GG + AG94 966 1.21007 0.76069 1.9249 0.42078 stroke G DOM 0.508 0.576 stroke GREC 0.500 0.420 0.450 AA + AG stroke G REC 0.500 0.450

What is claimed is:
 1. A method for treating noncardioembolic stroke ina human, the method comprising testing nucleic acid from said human fora polymorphism rs10757274 comprising G at position 101 of SEQ ID NO:1566or C at its complement, detecting a homozygous genotype of said G orsaid C to thereby identify said human as having an increased risk fornoncardioembolic stroke relative to not having said homozygous genotype,and administering a statin to treat noncardioembolic stroke to saidhuman.
 2. The method of claim 1, wherein said testing comprisesamplifying by polymerase chain reaction (PCR) a fragment of said nucleicacid that includes said polymorphism rs10757274 to thereby create anamplicon containing said polymorphism rs10757274.
 3. The method of claim1, wherein said testing comprises sequencing said nucleic acid.
 4. Themethod of claim 1, wherein said testing comprises contacting saidnucleic acid with an oligonucleotide that specifically hybridizes tosaid G or said C.
 5. The method of claim 4, wherein the nucleotidesequence of said oligonucleotide consists of a segment of at least 12contiguous nucleotides of SEQ ID NO:1566 or its complement and includessaid position
 101. 6. The method of claim 4, wherein saidoligonucleotide is detectably labeled with a fluorescent dye.
 7. Themethod of claim 4, wherein said oligonucleotide is an allele-specificprobe.
 8. The method of claim 4, wherein said oligonucleotide is anallele-specific primer.
 9. The method of claim 8, wherein saidallele-specific primer comprises the nucleotide sequence of SEQ IDNO:1757.
 10. A method for treating noncardioembolic stroke in a human,the method comprising testing nucleic acid from said human for apolymorphism rs10757274 comprising G at position 101 of SEQ ID NO:1566or C at its complement, detecting a heterozygous genotype of said G orsaid C to thereby identify said human as having an increasedresponsiveness to statin treatment for reducing stroke risk relative tonot having said heterozygous genotype, and administering a statin totreat noncardioembolic stroke to said human.
 11. The method of claim 10,wherein said testing comprises amplifying by polymerase chain reaction(PCR) a fragment of said nucleic acid that includes said polymorphismrs10757274 to thereby create an amplicon containing said polymorphismrs10757274.
 12. The method of claim 10, wherein said testing comprisessequencing said nucleic acid.
 13. The method of claim 10, wherein saidtesting comprises contacting said nucleic acid with an oligonucleotidethat specifically hybridizes to said G or said C.
 14. The method ofclaim 13, wherein the nucleotide sequence of said oligonucleotideconsists of a segment of at least 12 contiguous nucleotides of SEQ IDNO:1566 or its complement and includes said position
 101. 15. The methodof claim 13, wherein said oligonucleotide is detectably labeled with afluorescent dye.
 16. The method of claim 13, wherein saidoligonucleotide is an allele-specific probe.
 17. The method of claim 13,wherein said oligonucleotide is an allele-specific primer.
 18. Themethod of claim 17, wherein said allele-specific primer comprises thenucleotide sequence of SEQ ID NO:1757.